The French immediately launched a two-front offensive against Charles.
 In the north, the Duke of Orléans attacked Luxembourg, briefly capturing the city; in the south, a larger army under Claude d'Annebault and Francis's eldest son, the Dauphin Henry, unsuccessfully besieged the city of Perpignan in northern Spain.
 Francis himself was meanwhile in La Rochelle, dealing with a revolt caused by popular discontent with a proposed reform of the gabelle tax.

By this point, relations between Francis and Henry VIII were collapsing.
 Henry—already angered by the French refusal to pay the various pensions, which were owed to him under the terms of past treaties—was now faced with the potential of French interference in Scotland, where he was entangled in the midst of an attempt to marry his son to Mary, Queen of Scots, that would develop into the open warfare of the "Rough Wooing".
 He had intended to begin a war against Francis in the summer of 1543, but negotiating a treaty to that effect with the Emperor proved difficult; since Henry was, in Charles's eyes, a schismatic, the Emperor could not promise to defend him against attack, nor sign any treaty which referred to him as the head of the Church—both points upon which Henry insisted.
 Negotiations continued for weeks; finally, on 11 February 1543, Henry and Charles signed a treaty of offensive alliance, pledging to invade France within two years.
 In May, Henry sent Francis an ultimatum threatening war within twenty days; and, on 22 June, at last declared war.

Hostilities now flared up across northern France.
 On Henry's orders, Sir John Wallop crossed the Channel to Calais with an army of 5,000 men, to be used in the defense of the Low Countries.
 The French, under Antoine de Bourbon, Duke of Vendôme, had captured Lillers in April; by June, d'Annebault had taken Landrecies as well.
 Wilhelm of Cleves openly joined the war on Francis's side, invading Brabant, and fighting began in Artois and Hainaut.
 Francis inexplicably halted with his army near Rheims; in the meantime, Charles attacked Wilhelm of Cleves, invading the Duchy of Jülich and capturing Düren.

Concerned about the fate of his ally, Francis ordered the Duke of Orléans and d'Annebault to attack Luxembourg, which they took on 10 September; but it was too late for Wilhelm, as he had already surrendered on 7 September, signing the Treaty of Venlo with Charles.
 By the terms of this treaty, Wilhelm was to concede the overlordship of the Duchy of Guelders and County of Zutphen to Charles, and to assist him in suppressing the Reformation.
 Charles now advanced to besiege Landrecies, seeking battle with Francis; the French defenders of the town, commanded by Martin du Bellay, repulsed the Imperial attack, but Francis withdrew to Saint-Quentin on 4 November, leaving the Emperor free to march north and seize Cambrai.
The French immediately launched a two-front offensive against Charles.  In the north, the Duke of Orléans attacked Luxembourg, briefly capturing the city; in the south, a larger army under Claude d'Annebault and Francis's eldest son, the Dauphin Henry, unsuccessfully besieged the city of Perpignan in northern Spain.  Francis himself was meanwhile in La Rochelle, dealing with a revolt caused by popular discontent with a proposed reform of the gabelle tax.
By this point, relations between Francis and Henry VIII were collapsing.  Henry—already angered by the French refusal to pay the various pensions, which were owed to him under the terms of past treaties—was now faced with the potential of French interference in Scotland, where he was entangled in the midst of an attempt to marry his son to Mary, Queen of Scots, that would develop into the open warfare of the "Rough Wooing".  He had intended to begin a war against Francis in the summer of 1543, but negotiating a treaty to that effect with the Emperor proved difficult; since Henry was, in Charles's eyes, a schismatic, the Emperor could not promise to defend him against attack, nor sign any treaty which referred to him as the head of the Church—both points upon which Henry insisted.  Negotiations continued for weeks; finally, on 11 February 1543, Henry and Charles signed a treaty of offensive alliance, pledging to invade France within two years.  In May, Henry sent Francis an ultimatum threatening war within twenty days; and, on 22 June, at last declared war.
Hostilities now flared up across northern France.  On Henry's orders, Sir John Wallop crossed the Channel to Calais with an army of 5,000 men, to be used in the defense of the Low Countries.  The French, under Antoine de Bourbon, Duke of Vendôme, had captured Lillers in April; by June, d'Annebault had taken Landrecies as well.  Wilhelm of Cleves openly joined the war on Francis's side, invading Brabant, and fighting began in Artois and Hainaut.  Francis inexplicably halted with his army near Rheims; in the meantime, Charles attacked Wilhelm of Cleves, invading the Duchy of Jülich and capturing Düren.
Concerned about the fate of his ally, Francis ordered the Duke of Orléans and d'Annebault to attack Luxembourg, which they took on 10 September; but it was too late for Wilhelm, as he had already surrendered on 7 September, signing the Treaty of Venlo with Charles.  By the terms of this treaty, Wilhelm was to concede the overlordship of the Duchy of Guelders and County of Zutphen to Charles, and to assist him in suppressing the Reformation.  Charles now advanced to besiege Landrecies, seeking battle with Francis; the French defenders of the town, commanded by Martin du Bellay, repulsed the Imperial attack, but Francis withdrew to Saint-Quentin on 4 November, leaving the Emperor free to march north and seize Cambrai.
Italian War of 1542–1546