The Safavids entered into conflict with the Ottoman Empire in the Ottoman-Safavid War (1532–1555), forcing it to split its military resources.
Suleiman the Magnificent: Charles signed a humiliating treaty with the Ottomans to gain him some respite from the huge expenses of their war, in which he was seen as the equivalent of the Grand Vizier of the Ottoman Empire -Ibrahim Pasha at the time - and was referred to as only the King of Spain since there could only be one Emperor in the world and it was Suleiman.
Charles fought continually with the Ottoman Empire and its sultan, Suleiman the Magnificent.
In 1543 Charles allied himself with Henry VIII and forced Francis to sign the Truce of Crépy-en-Laonnois.
In 1536 Francis I of France allied himself with Suleiman against Charles. While Francis was persuaded to sign a peace treaty in 1538, he again allied himself with the Ottomans in 1542 in a Franco-Ottoman alliance.
The great Hungarian defeat at the 1526 Battle of Mohács "sent a wave of terror over Europe.
The Muslim advance in Central Europe, was halted at Vienna in 1529.
The Muslim Barbary corsairs, acting under the general authority and supervision of the Sultan, regularly devastated the Spanish and Italian coasts, crippling Spanish trade and chipping at the foundations of Habsburg power.
Charles V made overtures to the Safavid Empire to open a second front against the Ottomans, in an attempt at creating a Habsburg-Persian alliance.