I’d just like to confirm what everybody else has said: it is definitely do-able and definitely worth it! I had an 8-hour layover last year. For what it’s worth, here was my basic itinerary. (I should point out that I love walking, but there are public transport alternatives, noted below. A decent map will make this walk much easier if you’re not familiar with the area.)

I hopped on the LOCAL train headed to Fara Sabina (not the express to Termini, which as people have pointed out is not terribly interesting in its own right). It costs 5.50 euros to any Rome stop and there are at least two trains an hour during the day. Buy your return ticket at the same time and save a little time on your way back. I got off at Trastevere. From there I walked up viale di Trastevere (you can also take a number 8 tram or any bus headed in the same general direction). There are a few pretty churches, like Santa Maria in Trastevere, and the Piazza San Cosimato is as good a place as any to stop for a coffee. The little side streets are charming.

Push on towards the river and either cross at the Isola Tiberina or take the same bridge as the tram towards Largo Argentina. (Note the abandoned cats who live among the ruins there, and who are fed every day by volunteers.) Take in more colorful streets and alleys (Campo de’ Fiori to your left or the ghetto to your right).

Keep walking north into the centro storico and head to the stately, busy Piazza Navona and the Pantheon, and marvel at the architecture. Depending on the time of day and your state of hunger, stop for a coffee at Caffè Sant’Eustacchio, on the piazza of the same name, for the best coffee in Rome (the icy coffee granita may be just the pick-me-up you need if it’s hot out); go to Cul de Sac, piazza di Pasquino, just off the Piazza Navona, for a glass of wine and fine snacks; or stop at Maccheroni on the corner of piazza and via delle Coppelle for a more substantial, yet quick meal of pasta and meat.

Then veer towards the via del Corso and adjoining streets for a bit of window shopping. (If you have time to push as far as the Ara Pacis, do so, then walk down the Corso.)

On the other side of the Corso are the Spanish Steps. If you want to see the view from the top, you can climb the steps or take the elevator hidden beside the entrance to the metro to the left as you’re looking up at the steps. Back down at street level take a few more steps to the Trevi Fountain, spectacular despite the crowds of tourists you will encouter any time of the day or night. If you’re in the mood for the best ice cream in Rome, head to San Crispino, via della Pannetteria, a couple of streets from the fountain. (If you’re craving for more before your flight, there is a branch of San Crispino in Terminal A at Fiumicino.)

Veer towards Piazza Venezia. You can climb to the top of the Vittorio Emanuele monument or to the Capitoline Museums just behind it to the right – access to the café’s terrace is free, and offers a breathtaking view of the St. Peter’s. If you have time the museums’ collections are extensive, but that might be a bit time consuming.

From there wander down via dei Fiori Imperiali to the Coliseum. Wander into the ruins of the Forum if you like. The Coliseum itself is probably most spectacular seen from the outside.

At this point, you’ll probably need to think about getting back to the airport. From Coloseo, you’re two metro stops from Piramide (from which you’d have to walk a couple of hundred meters to Ostiense train station), a short bus ride to Ostiense station itself or about a half hour walk. From there, use your return ticket back to the airport.

Have a great, great time. I’ve fallen in love with Rome and this walk played a big part in my love affair with the city. I’m now back in Rome, my Italian is improving by leaps and bounds and I’m going to be here at least for the next few months. What more could I ask for?