It was however the Muslims who provoked the most dangerous event in Byzantine history, the sacking of Constantinople in 1204 by the crusaders. When the Seljuk Turks overran the Christian holy places, Pope Urban II (1088-99) preached on the need for a crusading movement of Christians to march against the infidel forces. Although Emperor Alexios I had appealed for military help and had made alliances with Venetian merchants, who were familiar figures the empire's ports, the arrival in Constantinople of pilgrims and mounted knights from northern Europe caused many anxieties in Byzantium. The western Christians did not worship in the same language or in the same way as the Orthodox: they used unleavened bread in the sacrament and recited a different wording of the creed; their bishops and monks all carried weapons and intended to fight, which seemed sacrilegious to the eastern Christians.

The initial co-operation between Latin- and Greek-speaking believers during the First Crusade rapidly gave way to mutual distrust. Through a series of accidents and miscalculations on both sides, Venice, which had the most to gain, encouraged the diversion of the Fourth Crusade. Instead of a sea-borne attack on Alexandria, the western forces sailed to Constantinople and sacked the city in 1204. This was a turning point in Byzantium's history which defined its particular character and divided it from the west forever. Loot from the city now adorns numerous western cathedral treasuries, particularly the church of San Marco in Venice.

In the west's bad faith over the capture of 1204 crusaders and religious authorities alike created a view which perpetuated the heretical nature of Byzantine Orthodoxy and the unworthy nature of an empire that had accumulated so much wealth in holy relics and art. This negative approach was greatly intensified by Enlightenment scholars such as Voltaire and Gibbon, who saw in Byzantium nothing but unproductive monks, sycophantic eunuch courtiers and feeble imperial leaders. One of the most important acts of modern times to counter this ill-informed attitude was Pope John Paul II's apology made in 2000 to the Patriarch of Constantinople for the capture of 1204.