One of the major theological disputes over the nature of Jesus Christ in the early years of the Byzantine Empire was the Monophysite controversy. The position expressed at the Council of Chalcedon in 451 was that Jesus Christ fully possessed two natures, divinity and humanity. However, those who will come to be called Monophysites by the supporters of Chalcedon believed that Jesus Christ possessed only one nature, divinity. It should be noted that those who believed that Jesus Christ possessed only one nature will not, however, call themselves Monophysites. They are known as the Coptic Orthodox Church today.

The supporters of the monophysite position were extremely numerous especially throughout the region of northern Africa and would establish their own ecclesiastical hierarchy as a rival to that of the Chalcedonians. So what began as a theological dispute would quickly have political repercussions as large sections of the Byzantine Empire placed themselves in opposition to imperial authority as long as the Emperor supported the theology of Chalcedon.

On 9 April 476, Emperor Basiliscus attempted to pacify the supporters of the Monophysite position by issuing his Enkyklikon, or encyclical letter, ordering that the decisions of the Council of Chalcedon and its supporting Letter of Pope Leo were to be rejected. All the bishops of the Empire were to sign this letter attesting their agreement to its decisions and Evagrius Scholasticus states that 500 bishops signed their names. However, Patriarch Acacius of Constantinople and most of the Constantinople opposed the Enkyklikon. They showed their hostility by covering the icons in the Basilica of Hagia Sophia in black cloth.

In the West, Pope Simplicius asserted that it was he as successor of Peter and not the Emperor who possessed the authority of expounding the faith. He too rejected the Enkyklikon.

In 477, Zeno expelled Basiliscus, rescinded the Enkiklikon and pronounced his support of Chalcedon. However, in 482 he will try his own hand at making peace among the different sides of this argument over the nature of Christ with the issuance of his Henotikon. This will result in the Acacian schism between the Eastern and Western Church.

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