In Vatican City, St. Peter's Basilica (Piazza San Pietro; open daily, 7 a.m. to 7 p.m.), the earthly locus of the Roman Catholic Church, and the extensive Vatican Museums (where you'll find the Sistine Chapel) are grouped together just across the Tiber River from central Rome. Visitors to St. Peter's and the Vatican Museums (open Monday to Saturday, 9 a.m. to 6 p.m.) have to clear a security checkpoint. The line for St. Peter's begins in the Piazza, while the entrance and line to the Vatican Museums is around the corner (to the left, on Viale Vaticano). Expect to wait in line for hours if you want to visit the Vatican Museums on your own. (One advantage to booking a cruise line tour is you might not have to wait quite that long.) Plan ahead, and book your tickets (timed entry) online to skip the lines; you'll only need to pass through security. It's easier to bypass lines if you enter through the museums, which lets you out in front of St. Peter's, where you may enter without further lines. However, there can be lines if you'd like to climb to the top of St. Peter's Basilica (or ride up in the elevator). While it's free to enter St. Peter's, the climb/ride carries a small fee, and entrance to the Vatican Museums is pricey (but well worth it, specifically to see the Sistine Chapel in person). The Vatican Gardens are available for viewing with tickets, as well, but note that these tickets may book up as far as six months in advance. Note: Vatican City is its own city and is not included in ROMA passes. Be aware that sleeveless shirts, shorts and short skirts or dresses are not acceptable attire within St. Peter's, and you will be banned from entering if you don't have a sufficient way to cover up. Bring a shawl, and be sure the attire on your lower half reaches at least to your knees.
The Colosseum (Piazza del Colosseo; open 9 a.m. and closing between 4 to 7 p.m., depending on the time of year) is the shell of an ancient stadium, first inaugurated in 80 A.D., where gladiators engaged in bloodbaths. The building is impressive, and you'll want to spend at least an hour taking it in. There are areas that are only accessible by foot and stairs, but there is also an elevator to reach the top. Across the street are the Roman Forum and Palatine Hill. Walking along the streets of the ancient ruins will transform you, as you envision what this central Italian piazza would have been like during the age of Caesar. Tickets to the Colosseum and Forum can be purchased together; lines are much shorter at the Forum ticket line.
Near the Colosseum, we always drop our jaws at the sight of the Vittorio Emanuele Monument (Piazza Venezia), an extravagant white-marble monument (nicknamed "the wedding cake") with giant horse sculptures, constructed in the 1800's to honor Italy's first king. You can't go inside, but it's a great photo opp.
The Pantheon (Piazza della Rotunda; open Monday to Saturday, 9 a.m. to 6:30 p.m., Sunday, 9 a.m. to 1 p.m.) dates back to 27 B.C. and is considered the ancient world's most complete monument. Even better, the Pantheon is more than a museum; it still holds concerts and other special events.
The Trevi Fountain (Piazza Trevi; open 24 hours) was made famous by the classic flick "Three Coins in a Fountain"; legend has it, if you want to come back to Rome, you must throw in a coin. Within walking distance are the Spanish Steps, which draw quite a crowd when the late afternoon sun begins to create a warm, golden hue over the 154 steps leading to the Trinita dei Monti. (If you can make the climb, a rooftop cafe awaits, offering wonderful views of the Roman skyline.)
For art-lovers, Galleria Borghese (Villa Borghese; open Tuesday to Saturday, 8:30 a.m. to 7:30 p.m.) has Rome's premier collection of masterpieces, including works by Titian, Caravaggio and Raphael.
Rome's most magnificent shops are clustered on streets branching off from the elegant Piazza d'Spagna (the Spanish Steps). The most chic stores are found on Via Veneto and Via Condotti; more mainstream (and affordable) stores are on the long Via del Corso. Take a coffee break at Antico Caffe Greco (Via dei Condotti 86), a place to see and be seen since it opened in 1760. Antique stores are clustered on Via del Babuino.