You can't miss Brunelleschi's magnificent dome atop the rosy marble Cathedral. It's the obvious central meeting point and tourist hub of the city. Here, you're in the vicinity of practically everything: the Uffizi Museums, Palazzo della Signoria, the San Lorenzo Market, and the Accademia.
The streets surrounding the Duomo cater to visitors, with generic, all-day dining (for a price), and exclusive shopping. The big guns in Italian fashion are located along Via Tornabuoni (technically closer to Santa Maria Novella), with several others on Via Calzaiuoli, Via del Corso. Borgo Albizi, which starts behind the Duomo is more a boutique street, featuring handmade, original designs in clothing and accessories. Souvenir shops abound, as do street performers, caricature artists, and tourist traps.
The glorious Palazzo Pitti and the Boboli Gardens make their home in Oltrarno, which literally means "beyond the Arno river." Cross over Ponte Vecchio, and into the only chaotic street in this otherwise tranquil, residential area. The bars around Piazza Santo Spirito are popular aperitivo places with the Florentines, and far more casual than the cafés and bars on the other side of the Arno.» See hotels in Oltrarno.
North of the train station is one of Florence's most colorful neighborhoods. San Lorenzo is home to much of the city's foreign population, many of whom man the stands at the bustling local market. The area is the cheapest place to shop and snack in the center of the city.
Peruse the stands wisely for real leather bags and accessories, and be on the look out for fakes. The streets around the market are home to kebab stands and Asian markets galore, as well as cheap clothing and shoe shops. San Lorenzo is also home to Fiaschetteria-Trattoria Mario, the real deal as far as authentic Florentine eating goes, miraculously unruined by fame. There's not one guidebook or magazine that hasn't plastered a logo on the front door.
North of the Duomo, and home to the Accademia and David, parts of this area are flooded with tourists and tourist cuisine. As you head north, however, the streets widen out a bit, and there's a much more residential feel to the area.
The university is also located nearby, which explains the few hipster-inspired bars, shops, and restaurants dotting the 'hood. You're most likely to find peace and quiet in the northern part of San Marco.
Named for the Santa Croce cathedral, which marks the center of this neighborhood, the south end of Santa Croce borders the Duomo and swarms with tourists. The piazza itself is actually a popular spot for Florentines to meet, chat and then head elsewhere for to eat. The parallel streets behind the church are relatively quiet, and slightly more residential.
Head north-east to Sant'Ambrogio, where Florence feels hipper, younger, and much more real. Via dei Neri, a cross street on the other side of Via de'Benci, the south-western border of the piazza, is lined with wine bars, specialty food shops and a few great osterias.
Across the street from the train station, the area around Piazza Santa Maria Novella is perhaps the most varied neighborhood in the city. The dingier urban streets leading to the station get a lot of traffic (both automobile and human) while the other side of the grassy Piazza is formed by narrow, serpentine little streets, characterful buildings and top-notch shopping. The piazza itself is crowded with picnicking tourists and pick pockets preying on them.
The 'hood is bordered by the river, the train station and the shopping street Via Tornabuoni. As such, this area suffers a bit of an identity crisis. One thing is for sure: once you're here, you're no more than ten-minutes away from anything else.