In 1526, Europe was in a state of constant motion, with countries making new alliances, competing for land, and fighting for power. One of the key events during this time was the increasing power of Emperor Charles V, the Holy Roman Emperor and the King of Spain. His growing power disturbed most of the European rulers, especially Francis I of France and Pope Clement VII. They viewed his dominance as a challenge to their ambitions and authority.

Francis I had been struggling with Charles V over land and power for many years. Following his defeat and capture at the Battle of Pavia in 1525, he was in a precarious position. The battle had been a significant victory for Charles V's army, resulting in Francis I being taken prisoner. He was forced to sign the Treaty of Madrid early in 1526. By this treaty, Francis surrendered huge tracts of land, such as Burgundy, to Charles V and agreed to other unfavorable terms. As soon as he was released, Francis I immediately repudiated the treaty. He said he had signed it under compulsion. To balance Charles V's authority, Francis I sought out Pope Clement VII, the leader of the Catholic Church and monarch of the Papal States. Clement VII was a Medici and was concerned about Charles V increasing his power in Italy, especially after he had taken over the Duchy of Milan. Francis I and Clement VII realized that they both had to limit Charles V's power, and thus they formed an alliance with other Italian city-states like the Republic of Venice, the Duchy of Milan, and England under Henry VIII. This league, which was organized in May of 1526, was called the League of Cognac.

The League of Cognac was mainly aimed at restoring a balance of power in Europe by challenging Charles V's dominance. The league prepared for a new war, leading to a further stage of the ongoing wars among the main power brokers in Europe: the Pope, the Emperor, and the King of France. This struggle would spawn a succession of wars waged with armed force, like the War of the League of Cognac, that made Italy a chief battleground. One of the most famous episodes connected with the League was the Sack of Rome in 1527. Charles V's army, which was made up to a great extent of unpaid and mutinous soldiers, violently attacked the city at that time. They devastated a great part of it and murdered many individuals.

The Pope was compelled to seek shelter in Castel Sant'Angelo before finally capitulating to Imperial troops. These appalling incidents greatly undermined the League of Cognac, enabling Charles V to continue his supremacy over Italy. Eventually, the League of Cognac was created to try to stop Charles V from gaining too much power, but it did not succeed in its goals in the long run. The subsequent war demonstrated the sharp differences in opinion among the leaders of Europe and set the stage for future conflicts. Although it was a good idea to start with, the League was short-lived in its challenge to Charles V's authority, and he would continue to shape European history for decades to come.