Nestorius was Archbishop of Constantinople from 10 April 428 to 22 June 431. Drawing on his studies at the School of Antioch he devised a doctrine that later bore his name; Nestorianism; which emphasized the disunity of the human and divine natures of Christ. His teachings; which included a rejection of the long-used title of Theotokos ("Mother of God") for the Virgin Mary; brought him into conflict with other prominent churchmen of the time; most notably Cyril of Alexandria; who accused him of heresy.

Nestorius sought to defend himself at the First Council of Ephesus in 431; but instead he found himself formally condemned for heresy and removed from his see. Thereafter he retired to a monaster; where he asserted his orthodoxy for the rest of his life. Despite his acquiescence; many of his supporters split with the rest of the church in the Nestorian Schism; and over the next decades a number of them relocated to Persia. Thereafter Nestorianism became the official position of the Church of the East.