Charles was the heir of three of Europe's leading dynasties: the Houses of Valois-Burgundy (through his paternal grandmother), Habsburg, and Trastámara (his maternal grandparents were the Catholic Monarchs of Spain). Charles inherited the Netherlands and the County of Burgundy as heir of the House of Valois-Burgundy. As a Habsburg, he inherited Austria and other lands in central Europe. He was also elected to succeed his grandfather, Maximilian I, as Holy Roman Emperor, a title held by the Habsburgs since 1452. From the Spanish House of Trastámara, he inherited (from his maternal grandmother Isabella I of Castile) the Crown of Castile, which was developing a nascent empire in the Americas and Asia, and (from his maternal grandfather Ferdinand II of Aragon) the Crown of Aragon, which included a Mediterranean empire extending to Southern Italy. Charles was the first king to rule Castile and Aragon simultaneously in his own right (as a unified Spain), and as a result he is often referred to as the first king of Spain. The personal union under Charles of the Holy Roman Empire with the Spanish Empire was the closest Europe would come to a universal monarchy since the death of Louis the Pious (778–840), the son of Charlemagne.
Because of widespread fears that his vast inheritance would lead to the realization of a universal monarchy and that he was trying to create a European hegemony, Charles was the object of hostility from many enemies. His reign was dominated by war and particularly by three major simultaneous conflicts: the Habsburg-Valois Wars with France, the struggle to halt the Ottoman advance, and the conflict with the German princes resulting from the Protestant Reformation. The wars with France, mainly fought in Italy, resulted in recovery of territory lost at the beginning of his reign and included the decisive defeat and capture of Francis I of France at the Battle of Pavia in 1525. France recovered and the wars continued for the remainder of Charles's reign. Enormously expensive, they led to the development of the first modern professional army in Europe, the Tercios.
The struggle with the Ottoman Empire was fought in Hungary and the Mediterranean. After crushing Hungarian forces in 1526, the Ottomans' advance was halted at their failed Siege of Vienna in 1529. A lengthy war of attrition, conducted on his behalf by his younger brother Ferdinand (who had become king of Hungary), continued for the rest of Charles's reign. In the Mediterranean, although there were some successes, Charles was unable to prevent the Ottomans' increasing naval dominance and the piratical activity of the Barbary corsairs. Charles opposed the Reformation and in Germany he was in conflict with the Protestant Princes of the Schmalkaldic League who were motivated by both religious and political opposition to him. He could not prevent the spread of Protestantism and although he won a decisive victory against the Princes at the Battle of Mühlberg, 1547, he was ultimately forced to concede the Peace of Augsburg of 1555, which divided Germany along denominational lines.
While Charles did not typically concern himself with rebellions, he was quick to put down three particularly dangerous rebellions in the vital territories of Castile, the Frisian lands, and later in his reign in the city of Ghent. Once the rebellions were quelled the essential Castilian and Burgundian territories remained mostly loyal to Charles throughout his rule.
Charles's Spanish dominions were the chief source of his power and wealth, and they became increasingly important as his reign progressed. In the Americas, Charles sanctioned the conquest by Castillian conquistadores of the Aztec and Inca empires. Castillian control was extended across much of South and Central America. The resulting vast expansion of territory and the flows of South American silver to Castile had profound long term effects on Spain.
Charles was only 56 when he abdicated, but after 40 years of energetic rule he was physically exhausted and sought the peace of a monastery, where he died at the age of 58. Upon Charles's abdications, the Holy Roman Empire was inherited by his younger brother Ferdinand, who had already been given the Austrian lands in 1521. The Spanish Empire, including the possessions in the Netherlands and Italy, was inherited by Charles's son Philip II of Spain. The two empires would remain allies until the 18th century (when the Spanish branch of the House of Habsburg became extinct).