I have often seen reference to the Four Holy Cities: Jerusalem, Hebron, Safed and Tiberias. What is the earliest source to reference this? Why these four cities? Has there ever been a different count? What are some Nafka Mina (relevant applications) of the status of these cities?
The 4 holy cities correspond to the 4 elements. Earth (Hebron) because of the cave of the patriarchs, Fire(Jeruselem) because of the temple sacrifices, Water(Tiveriah) because of lake Kineret, Air (Zfat) because it is high in the hills and the buildings being painted blue to keep out the evil eye and the spiritual, airy nature of kabalah which sprouted from the city.
There are some who say that they are reflect 4 temperaments of people, based on those elements, and that people are drawn to each city based on their temperament.
I can only assume that this comes from various statements within the Zohar and the Arizal. However, the status of the four cities as holy only became "well known" in the 1600s. While Zfat as the holy city of air , is mentioned in 1492. (source wikipedia)
The practical application of these 4 holy cities, is that various predictions regarding the Moshiach is made in reference to them, and Jewish people have asked to be buried in these four cities, even if they lived outside of Israel. More so than any other places in Israel.
Some conjecture on my part. I imagine that when coming to Israel in 1492, Tzfat was the only established (read protected) city that the exiles from Spain could return home to. (It's the only walled city in the north that I am aware of, that was not occupied by various armies and outposts)
Being that the people were Kabalists, and grew great inspiration from the place that they were, they gave it a certain holiness because of their hopes that it would be the beginning of the redemption.
However, knowing that it was not infact a holy city compared to other more important locations. (like nearby Tiveria, or the obvious home of their yearning, Jerusalem) they wanted to create a group of cities which Zfat could be part of. A group of four cities, each which have a very clear element associated with them would make for good drashot. And indeed, I have heard some great drashot over the years with this concept in mind.
Alternatviely, it's possible that Kabbalists required that Israel have a representation of each of the four elements within it's borders, and this was the driving force behind them assigning these cities. The fact that only Zfat on the list has no "intrinsic" holiness or meaning,(pre kabbalists moving there in 1492) leads me to the conjecture that I have just stated.