Just about everyone in the Western world knows that Jerusalem is a city that is holy to Jews. However, there are four holy cities in Eretz Yisrael (the land of Israel)!
The Four Holy Cities are Jerusalem, Tzfat (also known as Safed), Tiberius, and Hebron.
Jerusalem: Jerusalem is the center of the Jewish world. We pray towards Jerusalem (and within Jerusalem, towards the Temple Mount) at least three times per day, every day. It is where our First and Second Temples were located. One day, it is where the Third Temple will stand and where the priesthood will offer the required sacrifices. Some halachic laws only apply in Jerusalem. On both Yom Kippur and at the Passover seders, we conclude with the phrase, "Next year in Jerusalem!"
Tzfat: Tzfat is the home of kabalah and Jewish mysticism.
Tiberius: Tiberius is where the rabbis composed the Jerusalem Talmud. It became a large center of Jewish learning in the 18th and 19th centuries, at a point when when Jewish existence in the land of Israel was dangerous.
Hebron: Most of the patriarchs and matriarchs of Judaism (Avraham, Sarah, Isaac, Rebecca, Jacob, and Leah) are buried in Hebron at the Cave of the Patriarchs. Avraham purchased this land as a burial site for his family. Hebron was also King David's first capital before relocating to the City of David, which is in Jerusalem.