Martin Luther launched what later be known as the Reformation

In addition to conflicts between his Spanish and German inheritances, conflicts of religion would be another source of tension during the reign of Charles V. Before Charles's reign in the Holy Roman Empire began, in 1517, Martin Luther launched what would later be known as the Reformation. At this time, many local dukes saw it as a chance to oppose the hegemony of Emperor Charles V. The empire then became fatally divided along religious lines, with the north, the east, and many of the major cities – Strasbourg, Frankfurt, and Nuremberg – becoming Protestant while the southern and western regions largely remained Catholic.