This holy defender of the One, Holy, Catholic and Apostolic Church labored in the final days of the Byzantine Empire, when, pressed on all sides by the Turks, the Emperor in desperation sought union with (or rather submission to) the Papacy in hopes of obtaining aid from the West. It was St Mark who stood almost alone to prevent such a disaster to the Faith.

He was born in Constantinople in 1392 to devout parents. He received a thorough education and seemed destined for a secular career, but at the age of twenty- six he abandoned all worldly claims and became a monk in a small monastery in Nicomedia. Soon the Turkish threat forced him to return to Constantinople, where, continuing in the monastic life, he wrote a number of treatises on prayer and the dogmas of the Church. In time he was ordained priest, then, at the insistence of the Emperor John VIII Paleologos was made Metropolitan of Ephesus. The Emperor also prevailed on him to join the delegation which traveled to the Council of Florence to consider the reunion of the Orthodox Church and the churches under the Papacy. (Saint Mark went as exarch of the Patriarchs of Jerusalem, Antioch and Alexandria, who were unable to attend.)

The Greek delegation included the Emperor and the Patriarch of Constantinople. All, including Metropolitan Mark, began with great hopes that a true union in faith might result from the Council, but as the sessions proceeded, it soon became clear that Pope Eugenius and his theologians were interested only in securing submission of the Eastern Church to the Papacy and its theology. The Metropolitan spoke forcefully against various Latin dogmas such as the filioque and Purgatory, but the Greek delegation, desperate for western aid, bowed to expediency and agreed to sign a document of Union which would have denied the Orthodox Faith itself. Saint Mark was the only member of the delegation who refused to sign. When the Pope heard of this, he said "The bishop of Ephesus has not signed, so we have achieved nothing!"

When the delegation returned to Constantinople, the signers of the false Union were received with universal condemnation by the people, while Metropolitan Mark was hailed as a hero. The churches headed by Unionists were soon almost empty, while the people flocked to the churches headed by those loyal to Orthodoxy. Saint Mark left the City to avoid concelebrating with the Unionist Patriarch. He was exiled by the Emperor to Lemnos, but was freed in 1442. He continued to oppose the Union until his repose in 1444. In 1452 the Union was officially proclaimed in Constantinople, but the hoped-for Western aid was not forthcoming, and the City fell to the Turks in 1453.