The Truce of Nice, which ended the Italian War of 1536–1538, provided little resolution to the long conflict between the Holy Roman Emperor and the King of France; although hostilities had ended, giving way to a cautious entente, neither monarch was satisfied with the war's outcome.
 Francis continued to harbor a desire for the Duchy of Milan, to which he held a dynastic claim; Charles, for his part, insisted that Francis comply at last with the terms of the Treaty of Madrid, which had been forced on the French king during his captivity in Spain after the Italian War of 1521–26.
 Other conflicting claims to various territories—Charles's to Burgundy and Francis's to Naples and Flanders, among others—remained a matter of contention as well.

Negotiations between the two powers continued through 1538 and into 1539.
 In 1539, Francis invited Charles—who faced a rebellion in the Low Countries—to travel through France on his way north from Spain.
 Charles accepted, and was richly received; but while he was willing to discuss religious matters with his host—the Protestant Reformation being underway—he delayed on the question of political differences, and nothing had been decided by the time he left French territory.

In March 1540, Charles proposed to settle the matter by having Maria of Spain marry Francis's younger son, the Duke of Orléans; the two would then inherit the Netherlands, Burgundy, and Charolais after the Emperor's death.
 Francis, meanwhile, was to renounce his claims to the duchies of Milan and Savoy, ratify the treaties of Madrid and Cambrai, and join an alliance with Charles.
 Francis, considering the loss of Milan too large a price to pay for future possession of the Netherlands and unwilling to ratify the treaties in any case, made his own offer; on 24 April, he agreed to surrender the Milanese claim in exchange for immediate receipt of the Netherlands.
 The negotiations continued for weeks, but made no progress, and were abandoned in June 1540.

Francis soon began gathering new allies to his cause.
 William, Duke of Jülich-Cleves-Berg, who was engaged in the Guelders Wars, a dispute with Charles over the succession in Guelders, sealed his alliance with Francis by marrying Francis's niece, Jeanne d'Albret.
 Francis sought an alliance with the Schmalkaldic League as well, but the League demurred; by 1542, the remaining potential French allies in northern Germany had reached their own understandings with the Emperor.
French efforts farther east were more fruitful, leading to a renewed Franco-Ottoman alliance; Suleiman the Magnificent of the Ottoman Empire, seeking to distract Charles from Ottoman advances in Hungary, encouraged the Franco-Imperial rift.

On 4 July 1541, however, the French ambassador to the Ottoman court, Antoine de Rincon, was killed by Imperial troops as he was travelling near Pavia.
 In response to Francis's protests, Charles denied all responsibility, promising to conduct an inquiry with the assistance of the Pope; he had by now formed plans for a campaign in North Africa, and wished to avoid further entanglements in Europe.

By the end of September, Charles was in Majorca, preparing an attack on Algiers; Francis, considering it impolitic to attack a fellow Christian who was fighting the Muslims, promised not to declare war for as long as the Emperor was campaigning.
 The Imperial expedition, however, was entirely unsuccessful; storms scattered the invasion fleet soon after the initial landing, and Charles had returned to Spain with the remainder of his troops by November.
 On 8 March 1542, the new French ambassador, Antoine Escalin des Eymars, returned from Constantinople with promises of Ottoman aid in a war against Charles.
 Francis declared war on 12 July, naming various injuries as the causes; among them was Rincon's murder, which he proclaimed "an injury so great, so detestable and so strange to those who bear the title and quality of prince that it cannot be in any way forgiven, suffered or endured".
The Truce of Nice, which ended the Italian War of 1536–1538, provided little resolution to the long conflict between the Holy Roman Emperor and the King of France; although hostilities had ended, giving way to a cautious entente, neither monarch was satisfied with the war's outcome.  Francis continued to harbor a desire for the Duchy of Milan, to which he held a dynastic claim; Charles, for his part, insisted that Francis comply at last with the terms of the Treaty of Madrid, which had been forced on the French king during his captivity in Spain after the Italian War of 1521–26.  Other conflicting claims to various territories—Charles's to Burgundy and Francis's to Naples and Flanders, among others—remained a matter of contention as well.
Negotiations between the two powers continued through 1538 and into 1539.  In 1539, Francis invited Charles—who faced a rebellion in the Low Countries—to travel through France on his way north from Spain.  Charles accepted, and was richly received; but while he was willing to discuss religious matters with his host—the Protestant Reformation being underway—he delayed on the question of political differences, and nothing had been decided by the time he left French territory.
In March 1540, Charles proposed to settle the matter by having Maria of Spain marry Francis's younger son, the Duke of Orléans; the two would then inherit the Netherlands, Burgundy, and Charolais after the Emperor's death.  Francis, meanwhile, was to renounce his claims to the duchies of Milan and Savoy, ratify the treaties of Madrid and Cambrai, and join an alliance with Charles.  Francis, considering the loss of Milan too large a price to pay for future possession of the Netherlands and unwilling to ratify the treaties in any case, made his own offer; on 24 April, he agreed to surrender the Milanese claim in exchange for immediate receipt of the Netherlands.  The negotiations continued for weeks, but made no progress, and were abandoned in June 1540.
Francis soon began gathering new allies to his cause.  William, Duke of Jülich-Cleves-Berg, who was engaged in the Guelders Wars, a dispute with Charles over the succession in Guelders, sealed his alliance with Francis by marrying Francis's niece, Jeanne d'Albret.  Francis sought an alliance with the Schmalkaldic League as well, but the League demurred; by 1542, the remaining potential French allies in northern Germany had reached their own understandings with the Emperor. French efforts farther east were more fruitful, leading to a renewed Franco-Ottoman alliance; Suleiman the Magnificent of the Ottoman Empire, seeking to distract Charles from Ottoman advances in Hungary, encouraged the Franco-Imperial rift.
On 4 July 1541, however, the French ambassador to the Ottoman court, Antoine de Rincon, was killed by Imperial troops as he was travelling near Pavia.  In response to Francis's protests, Charles denied all responsibility, promising to conduct an inquiry with the assistance of the Pope; he had by now formed plans for a campaign in North Africa, and wished to avoid further entanglements in Europe.
By the end of September, Charles was in Majorca, preparing an attack on Algiers; Francis, considering it impolitic to attack a fellow Christian who was fighting the Muslims, promised not to declare war for as long as the Emperor was campaigning.  The Imperial expedition, however, was entirely unsuccessful; storms scattered the invasion fleet soon after the initial landing, and Charles had returned to Spain with the remainder of his troops by November.  On 8 March 1542, the new French ambassador, Antoine Escalin des Eymars, returned from Constantinople with promises of Ottoman aid in a war against Charles.  Francis declared war on 12 July, naming various injuries as the causes; among them was Rincon's murder, which he proclaimed "an injury so great, so detestable and so strange to those who bear the title and quality of prince that it cannot be in any way forgiven, suffered or endured".
Italian War of 1542–1546