Following the conquest of the Holy Land by the Ottoman Empire, larger numbers of Jews settled there. The population in Safed grew by leaps and bounds between 1525 and 1555. In 1525, there were 48 families. By 1555 there were 467. The community consisted mostly of Spanish and Portuguese Jews.
The famous Kabbalists Rabbi Yitzchak Luria (HaAri) and Rabbi Shlomo Alkabetz (the author of Lecha Dodi) lived in Safed. The first printing press in the Ottoman Empire was established in Safed in 1577 by Eliezer Ashkenaz. Joseph Karo, the author of the Shulchan Aruch (a codification of Jewish law), was also a resident of Safed.