After the Arian crisis of the fourth century, theologians started to discuss the nature of the humanity of Christ. Among them was of Laodicia, one of the participants of the of , who suggested that if Jesus is the true God then he could not be a perfect man. At the School of Antioch, of Mopsuestia taught the coexistence of two different natures in Christ, which would make it acceptable that the human nature of was born from the Virgin and had been crucified.

When the seat of Constantinople became vacant after the death of Sisinius in 427, Emperor Theodosius II decided to nominate a popular preacher from Antioch named Nestorius. Although he appears to have been a good monk, Nestorius was not a good theologian. He was also narrow-minded and he started to persecute the Arians, who had been tolerated by his predecessors.

He also defended the theological point of view of the School of Antioch but in his homily he mentioned that the Virgin should not be called the of God (Theotokos) but the Mother of (Christotokos). This assertion upset many people, including Proclus of Cizicus. He also entered into a contention with the Empress Pulcheria when he reproached her behavior.

In the same year (428), Cyril of Alexandria sent his famous letter to the monks, where he explained the mystery of and how it is suitable to call the Virgin the of God, although Cyril avoided mentioning Nestorius. But Nestorius unwisely received the complaints of some monks coming from Egypt. Worse, he did not send the synodical letter to his Alexandrian counterpart.

The Pope Celestinus (422-432) then became involved in the matter; both Cyril and Nestorius submitted to him the relevant documents. The documents of Cyril were translated into Latin while Nestorius’ documents were in Greek, and required some time and effort to be translated in Rome. Celestinus sided with the Alexandrian point of view.

Cyril wrote a letter to Nestorius, asking him to sign it within 10 days. This letter included his Twelve . Pulcheria supported the -Alexandrian popes while the emperor and his wife supported Nestorius. The situation became more confused, so the emperor ordered the convocation of a in Ephesus on 7 June 431. The choice of this city was not favorable to Nestorius.

Memnon, the bishop of the city, was not happy that the See of Constantinople had risen in stature above his own see since the Council of Constantinople in 381. Cyril presided over the with the support of Memnon, and John of Antioch was late in coming to the city. Nestorius was condemned by the council, but upon the arrival of John of Antioch and his Syrian colleagues, they declared that this condemnation was void and proceeded to excommunicate Cyril and Memnon.

The emperor decided to send both parties into exile, banishing Cyril, Memnon, and Nestorius. Cyril fled to Alexandria and Nestorius was exiled to Antioch first and after that to the Great Oasis (Kharga) in Upper Egypt, where he spent the rest of his life. After a long discussion between Cyril of Alexandria and John of Antioch, the relations between the two seats were restored. From the correspondence between these two patriarchs emerged a definition of that was accepted by everybody. See also SECOND OF EPHESUS.