Cyril was born around 375-80 in Alexandria, where he probably received his education, and he may have spent some time as a monk, though this is disputed. Though a great deal of Cyril's exegetic work is lost, much remains. On the Pentateuch there are two complementary works: Adoration and Worship in Spirit and in Truth and his Glaphyra. The former is a dialogue in which Cyril provides interpretation of various texts from the Pentateuch, presented in a thematic order. The Glaphyra discusses much the same texts in a continuous exposition, treating the texts in their biblical order. The writings from the period of the Nestorian controversy onwards are dominated by his opposition to Nestorianism. They include, however, Against the Godless Julian, a massive refutation of the apostate emperor's attack on Christianity. The anti-Nestorian writings take a variety of forms. Many of them are letters: to Nestorius himself, to Acacius, bishop of Melitene, to Eulogius, to Succensus, and others.

Jerusalem was raised to patriarchal status, in return for Juvenal's compliance with imperial orthodoxy, at the Council of Chalcedon and the real development of Palestinian monasticism belongs to the fifth century with the foundations of St Euthymius and St Sabas, the heroes of Cyril of Scythopolis' Lives of the Monks of Palestine. Jerusalem was marginal to the theological currents of the fourth and fifth centuries, and though it became a geographical focus for the controversy over Origenism, this was largely because of the presence in the Holy Land of Jerome and other Latins, who can hardly be classed as Palestinian, even though Jerome spent almost half his long life there. Cyril's main literary work is a collection of Catechetical Homilies. In the 390s Epiphanius was instrumental in fomenting the Origenist controversy in Palestine, and securing the support of Jerome, once an admirer of the great Alexandrian.