Governed from 1115 by an autonomous commune, the city was plunged into internal strife by the 13th-century struggle between the Ghibellines, supporters of the German emperor, and the Guelphs siding with the Pope, who after their victory split in turn into "White" and "Black" factions led respectively by Vieri de Cerchi and Corso Donati. These struggles led to the exile of the White Guelphs, one of whom was Dante Alighieri.

In spite of the long political conflict became one of the most powerful in Europe, assisted by her own strong gold currency, the florin (introduced in 1252), the eclipse of her formerly rival Pisa (defeated by Genoa in 1284 and subjugated by Florence in 1406), and the rule of its mercantile elite.

Of a population estimated at 80,000 before the Black Death of 1348, 25,000 were supported by the wool trade: in 1345 there was an attempted strike by wool combers (ciompi), who in 1378 rose up in a brief revolt against oligarchic rule in the Revolt of the Ciompi. After their suppression, the city was for some decades (1382-1434) under the sway of the Albizzi family, rivals of the Medici.

Cosimo de' Medici was the first Medici family member to control the city from behind the scenes, his power coming from a vast patronage network and his alliance to the new immigrants, the "gente nuova". Cosimo was succeeded by his son Piero, who was in 1469 succeeded by Cosimo's grandson, Lorenzo, a great patron of artists including Michel Angelo, Leonardo da Vinci and Botticelli.

Another great Florentine of the time was Niccolò Machiavelli, whose prescriptions for Florence's regeneration under strong leadership have often been seen as a legitimisation of political expediency and even malpractice. Commissioned by the Medici, Machiavelli wrote the Florentine Histories.

The city drove out the Medici for a second time and re-established a republic on May 16, 1527. Restored with the support of both Emperor and Pope, the Medici in 1537 became hereditary dukes of Florence, and in 1569 Grand Dukes of Tuscany, ruling for two centuries. Only the Republic of Lucca (later a Duchy) was independent from Florence in all Tuscany.

Florence replaced Turin as Italy's capital from 1865 until 1870. After doubling during the 19th century, Florence's population tripled in the 20th century with the growth of tourism, trade, financial services and industry.

During World War II the city experienced a year-long German occupation (1943-1944). The Allied soldiers who died driving the Germans from Tuscany are buried in cemeteries outside the city.