During the early 5th century, the School of Edessa had taught a Christological perspective stating that Christ's divine and human nature were distinct persons. A particular consequence of this perspective was that Mary could not be properly called the mother of God but could only be considered the mother of Christ. The most widely known proponent of this viewpoint was the Patriarch of Constantinople Nestorius. Since referring to Mary as the mother of God had become popular in many parts of the Church this became a divisive issue.

The Roman Emperor Theodosius II called for the Council of Ephesus (431), with the intention of settling the issue. The council ultimately rejected Nestorius' view. Many churches who followed the Nestorian viewpoint broke away from the Roman Church, causing a major schism. The Nestorian churches were persecuted, and many followers fled to the Sasanian Empire where they were accepted. The Sasanian (Persian) Empire had many Christian converts early in its history, tied closely to the Syriac branch of Christianity. The Sasanian Empire was officially Zoroastrian and maintained a strict adherence to this faith, in part to distinguish itself from the religion of the Roman Empire (originally the Greco-Roman Paganism and then Christianity). Christianity became tolerated in the Sasanian Empire, and as the Roman Empire increasingly exiled heretics during the 4th and 6th centuries, the Sasanian Christian community grew rapidly. By the end of the 5th century, the Persian Church was firmly established and had become independent of the Roman Church. This church evolved into what is today known as the Church of the East.

In 451, the Council of Chalcedon was held to further clarify the Christological issues surrounding Nestorianism. The council ultimately stated that Christ's divine and human nature were separate but both part of a single entity, a viewpoint rejected by many churches who called themselves miaphysites. The resulting schism created a communion of churches, including the Armenian, Syrian, and Egyptian churches. Though efforts were made at reconciliation in the next few centuries, the schism remained permanent, resulting in what is today known as Oriental Orthodoxy.