In the early sixteenth century two dynastic states struggled for mastery over western Europe. At first it was the Valois kings of France, who seemed poised to become the arbiters of Europe, after expelling their English rivals from the Continent, vanquishing their overmighty Burgundian vassals, and forging a centralized state out of their feudal jigsaw puzzle. Their attempts to conquer Italy were only barely held in check by the Italian powers, the Holy Roman (i.e. German) emperor, and the newly unified Kingdom of Spain.

In 1516, however, the crown of united Spain was inherited by Charles Habsburg, who was also head of the House of Austria, ruler of the Low Countries, and from 1519 Holy Roman emperor. The same year that Charles became emperor, the Spanish adventurer Hernando Cortés landed in Mexico, and soon a stream of treasure from the New World began to enrich Habsburg coffers in Europe.

By the mid-1520s France was thrown on the defensive, encircled by Habsburg territories from the north, south-east, and south-west. The first war between King François I of France and Charles V ended with the battle of Pavia (1525), in which the French army was annihilated and François himself taken prisoner. The captive king signed the humiliating treaty of Madrid in 1526, but repudiated it immediately after being set free. In the second war the French suffered a succession of defeats, and managed to hold their own thanks only to the help of the schismatic Protestant princes of Germany and of the infidel Ottoman Turks, both of whom were alarmed by the rising power of the Habsburgs. In 1529 Charles V, anxious about the Ottoman threat, granted France a tolerable peace at Cambrai.