In 1160, construction of Geneva’s Cathedrale St-Pierre began and was not completed until 1232. In the 15th Century, Geneva gained international renown through its trade fairs, which significantly contributed to the city's prosperity and fame.

Between the 13th and 17th Centuries, Geneva's independence was threatened by the Princes of Savoy, who frequently attacked the town. However, around 1530, because of support from the Swiss cantons of Bern and Fribourg, it preserved its autonomy.

In 1535, the Reformation triumphed, and the same year Geneva was proclaimed a republic. Later, John Calvin made the city his home, assisting in its recognition as Protestant Rome. After 1550, French and Italian Protestants, fleeing persecution, flooded Geneva, significantly influencing and transforming the city's art and culture, as well as facilitating an economic boom, from Geneva’s recession since the decline of the medieval fairs.

John Knox, an important collaborator on the Geneva Bible, preached in the city in 1555, and John Calvin established his academy in Geneva four years later, which formed the basis of the present university. Unfortunately, the city was not free of problems, as in 1602 conflict arose between Geneva and Savoy. Duke Charles Emmanuel of Savoy launched an unsuccessful attack against the city, known as the Escalade (scaling the walls), which is commemorated each year by a patriotic festival held in December. In the late 17th Century, a second wave of French Protestant immigrants flooded the city.