It appears that Charles' greatest threat and opposition came from the French in the form of Francis Valois. In 1515 when he came to the throne he was only 15 but was determined to be a major power in Europe. Roberts, a historian describes his main aims, when he first came to the throne, as being "to enhance his own and France's reputation through success in battle" and "to reassert the French claim to Milan." He wanted to consolidate his power, but his main aim was to gain Milan. However, after Charles became the most powerful figure in Europe Francis' aims soon changed and he was ready to do everything he could to stop Charles. "Francis would never accept Charles' claim to leadership of Christendom."
When Charles "the bold" died in 1477 he left no son to inherit the title to Burgundy and so his daughter, Mary, took the title of Duke of Burgundy.
Mary was then married to Maximillion, who was from the Hapsburg family and so eventually this title was passed onto Charles. However, the King of France, who at the time was Francis, was his overlord. This meant that although the title to the land was in the Hapsburg family, the possession of the land was in the Valois family. Francis wanted this land to be part of his lands and so in 1521 he tried to get it back by distracting Charles. He did this by asking a Burgundian nobleman, Robert De La Marck, to launch an assault on Luxemburg. However, Charles managed to distract Francis from this plan by signing the Treaty of Bruges with Henry VIII. In this treaty Henry agreed to invade Calais and so Francis' attention was sidetracked.
As a "key issue for Francis was Milan", he was keen to take...