
I like to imagine that the expression "when in Rome" was coined by someone very eager to partake of the Roman lifestyle: great food, rich culture and beautiful, historic architecture wherever you look. Its very long history, two and a half thousand years, leads to Rome's name, "The Eternal City," or, perhaps it's because once you visit, you never want to leave.

See:
• The Sistine Chapel: It's perhaps the most famous work of art in the world, so don't miss it. The Vatican museums are smartly designed so you can slowly wander for hours or speed straight through to reach the chapel. While you're there, stop by and say hi to the Pope.
• Villa Borghese: This former estate, just north of the center of Rome, began as a vineyard but is now publicly owned. The grounds include lovely gardens with grassy knolls, shady paths, a small lake and even a zoo. You can stroll, feed the turtles or rent a bike.
• Ponte Sant'Angelo: A beautiful, ancient bridge across the Tiber. It's decorated with ten angel statues sculpted by Bernini, his last work before his death. Now the bridge is for pedestrians only, and walking across it provides some great views of Rome.
• La Bocca della Verita (the mouth of truth): This is worth a visit just so you can pretend to be Audrey Hepburn in Roman Holiday. It's located in the Church of Santa Maria in Cosmedin. Legend has it that if you put your hand in the mouth and tell a lie, it'll bite off your hand. I've never been brave enough to fib and see for myself.
• The Pantheon: It's a structural triumph and a design lover's dream. The world's largest unsupported dome is made possible by coffers (molded concrete), which lighten the weight while still providing strength. They're functional but also amazingly beautiful, especially with the beam of light coming through the open oculus in the ceiling.

Tour:
• Galleria Borghese: This museum is located in the 17th century Villa Borghese and houses works by many Italian artists, but the real stars are the Bernini sculptures on the lower level. You must reserve tickets ahead and visits are limited to two hours, but you can always stroll the gardens (see above) before or after you get your fill of art.
• Keats-Shelley Memorial House: If you love the romantic poets and the macabre, check this out. The memorial house and working library is at the base of the Spanish Steps and houses mementos like a lock of Keats' hair and an urn filled with Shelley's cremated bones. Both men died in Italy, Keats of tuberculosis in 1821, while Shelley drowned a year later with a copy of Keats' poems in his pocket.
• Pasta Museum: Can't get enough pasta? The Romans know how you feel. This museum covers everything you'd ever want to know, from types of flour to cooking techniques to pasta machinery through the years. There's a ton of information, perhaps too much for the average pasta enthusiast, but you'll definitely be ready for lunch.
• The Colosseum: It may seem like another tourist trap, but do brave the crowds. The ancient amphitheater is both structurally and historically fascinating, especially now that the floor of the arena has disintegrated, exposing the labyrinth of tunnels that once held animals and gladiators before their fights.

Shop:
• Porta Portese: A huge and popular flea market, selling everything from antiques to clothing to oddities of all kinds. It's open only on Sunday mornings until 2 pm. Get there early (read: dawn) to get first dibs and avoid the crowds.
• Via Condotti: This shopping street begins at the base of the Spanish Steps and is lined with upscale shops like Valentino, Bulgari, Armani, Gucci and Prada, to name a few. It can be crowded with tourists, but it's worth a stroll if only for some very glam window shopping.
• Campo de' Fiori: This daily market, in the square of the same name, has been in business since 1869. It's packed with stalls selling fruits and veggies, meats and fish, and mountains of dried fruits, nuts and grains. They also sell flowers, although the name is thought to derive from Campus Florae (Flora's Square), named after Flora, the lover of the famous general Pompey.

Eat:
• Pizzeria Baffetto: The best pizza in Rome (Yep, I said it). Near the Piazza Navona, look for the line out the door of this small pizzeria. Fun fact: Baffetto means "chief capitan" and has become the nickname for the adorable owner of this joint.
• Il Gelato di San Crispino: No gelato is bad gelato but this is spectacular. There are multiple locations but my favorite is near the Trevi Fountain. Nothing feels more Roman than throwing a coin in the fountain (to ensure your return to Rome) and enjoying some stracciatella.
• Il Sapori del Lord Byron: If you're celebrating, this sexy restaurant is located inside the Hotel Lord Byron and recalls all the romance of its namesake. It's definitely upscale and reserved, but the menu is creative, seasonal and perfectly Italian.
• Sant' Eustachio: This café has been serving espresso since 1938, and they sure know how to do it right: it's thick and creamy, almost sweet. The building itself is still in full 30's glamour; you can't miss the gorgeous floor mosaics.
• Trattoria Da Gino: In central Rome, near the Piazza de Parlamento, is this small, hidden trattoria. They're known for classic Roman dishes, including the best handmade pasta you're likely to taste. Make sure to reserve a table because it's always crowded with locals and tourists alike. 
Stay:
• St. Regis Grand: This historic hotel was built by César Ritz in 1894 and has been housing royalty and the well-to-do ever since (they even have a diplomatic entrance). It's a splurge, but it's truly luxurious and worth a visit, even if it's just to the very stylish bar for a Compari.
• Ripa Hotel: Located in the trendy Trastevere district, most sights you want to see are a short walk or bus ride away. The rooms are spacious and many have lovely balconies, great for people watching. The style is modern and colorful, almost quirky.
• Inn at the Spanish Steps: This building was the former home of Hans Christian Andersen and is now a charming and upscale inn. The rooms are furnished in classic Roman décor so you feel like Sophia Loren.
• The First Hotel: Just across the river from Vatican City, this serene, modern hotel is as central as you can get, and the rooftop restaurant has views to die for.
(Images: 1.Flickr user Heatheronhertravels licensed for use under Creative Commons. 2.Flickr user xiquinho licensed for use under Creative Commons. 3. Shutterstock 4.Shutterstock 5.Shutterstock 6.Inn at the Spanish Steps)

White Enamel Flatwa...
Rome...one has to live there among other missions in life...but this one you cannot skip..
This could not have come at a better time, AT! We are going on our honeymoon to Europe soon and Rome will be one of the cities we visit. I've also been reading the other design guides to Athens/Santorini and Florence and have gathered many many great ideas for our trip. Thanks!
The Pantheon is amazing, and incredibly, FREE.
@sandinmyunderpants Boingboing had an "Underground Rome" post a while back. If you think you might like to do a hardhat tour of Nero's palace or check out the catacombs underneath the Vatican, I highly recommend spending the time to find the post and make reservations.
Rome is probably my very favorite city. I'd love to live there someday.
One of the best things my husband and I did in Rome while on our honeymoon a few years ago was just to walk with no real destination in mind...we wandered the city randomly, finding charming little pockets of awesomeness probably not in any guide book. Worth mentioning, oddly, is the rampant graffiti all over the city...some of it really beautiful, especially juxtaposed with the patina of ancient streets and buildings.
But yeah...definitely hit the more "touristy" spots like the Colosseum, Vatican, Pantheon, etc. So amazing, and worth the heavier crowds and/or entry fees.
There's nothing like Rome. :)
I highly recommend The Tempietto by Bramante on the Janiculum Hill, just above Trastevere. It's set in the peaceful little cloister of San Pietro in Montorio.
The pizzeria Il Baffetto is totally worth the wait! Don't let the line intimidate you - it goes quickly. Baffetto means "little mustache", BTW. Part of the joke is that it's a little bit Hitler-ish (in a Mel Brooks style of humor).
Also, I think one of the best food deals in Rome is a Tavola Calda (hot table, but really Italian fast food)... It's a lunch counter with hot meals. You buy items by the plate -- similar to the IKEA cafeteria but more homey -- anything from Osso Buco to salads to spaghetti. There is always a huge variety and I haven't eaten badly yet! I love the retro vibe of Canova in the Piazza del Popolo. It's a little more pricey. There are also a bunch in the neighborhood between the Vatican and the Tiber River.
Also a beautiful bakery: Forno Campo de'Fiori. The printed paper bread wrappers are well-designed and the bread is good! You can also get fairly cheap beer - per portare via/ to go - in this square (beer is expensive in Italy).
Caffe' Sant'Eustachio sells some super cool crockery - creamers, pitchers and teapots with their stag head logo (looks like the Jägermeister logo).
The coffeshop Tazza D'Oro near the Pantheon is also worth checking out - totally retro design.
The Porta Portese Flea market is easily accessible and pretty decent. I can always manage to find something I like, but next time, we'll probably try out some other places. It wasn't the Holy Grail of flea markets for me.
A really pretty street near the Spanish Steps: Via Margutta. It's short and sweet. Fellini lived here.
Just a minor correction/addition (lived in Rome for 7 years so I have a little insight...) on the coffee recommendation.
Piazza Sant'Eustachio is close to the Pantheon and well worth the SHORT walk, especially for coffee fans. Bar Sant'Eustachio, mentioned in the article, is famous for their cappuccino, not really for their espresso. They have all these blinders up so you can't see the "secret" way they make it. LOL It is pre-sweetened, so you get a good cappuccino that is nice and sweet and hard not to like. The blinders are a tourist gag, but it's still a cool place and the coffee is legit.
In the SAME PIAZZA, there is also Bar Camilloni. After you have fun at Bar Sant'Eustachio, it's time to get serious at Camilloni! LOL The espresso THERE is legendary, especially the "ristretto" (restrained), which is an especially "short" and concentrated espresso. Ristretto is to espresso what espresso is to a regular cup of joe.
I've sent MANY people into the clutches of this beautiful, simple, off the beaten path piazza and they've all thanked me for it, so make sure you don't miss out on half the attraction of that short walk!
My family and I just returned from a trip to rome. Agree with all of the recommendations above. We stayed at the inn at the Spanish steps.its fantastic! Plus just one block from the spagna metro station
One of the most beautiful place in the world, for it livelyhood!! Once again let down your guide and get lost!
It is the contrary of an aseptized city!
Design lovers in Rome shouldn't miss MAXXI, the National Museum of XXI Century Arts.
The building, designed by Zaha Hadid, is a major architectural work and it really worths a visit. http://www.fondazionemaxxi.it/?lang=en