[[File:Europe As A Queen Sebastian Munster 1570.jpg|thumb|200px|''[[Europa regina]]'', associated with a Habsburg-dominated Europe under Charles V.]]
Πιθανόν πιο σημαντική για τη στρατηγική του Ισπανού βασιλιά, η Ένωση είχε συμμαχήσει με τους Γάλλους, και προσπάθειες στη Γερμανία να υποσκαφθεί η Ένωση απορρίφθηκαν. Η ήττα του Φραγκίσκου το οδήγησε στην ακύρωση της συμμαχίας με τους Προτεστάντες, και ο
Κάρολοςook advantage of the opportunity. He first tried the path of negotiation at the [[ Council of Trent]] in 1545, but the Protestant leadership, feeling betrayed by the stance taken by the Catholics at the Council, went to war, led by the Saxon [[Elector of Saxony|elector]] [[Maurice of Saxony|Maurice]]. In response, Charles invaded Germany at the head of a mixed Dutch-Spanish army, hoping to restore the Imperial authority. The Emperor personally inflicted a decisive defeat on the Protestants at the historic [[Battle of Mühlberg]] in 1547. In 1555, Charles signed the [[Peace of Augsburg]] with the Protestant states and restored stability in Germany on his principle of ''[[cuius regio, eius religio]]'' ("whose realm, his religion"), a position unpopular with the Spanish and Italian clergy. Charles's involvement in Germany would establish a role for Spain as protector of the Catholic Habsburg cause in the Holy Roman Empire; the precedent would lead, seven decades later, to involvement in the war that decisively ended Spain's status as Europe's leading power.
In 1526, Charles married [[Isabella of Portugal|Infanta Isabella]], the sister of [[John III of Portugal]]. In 1556 he abdicated from his positions, giving his Spanish empire to his only surviving son, [[Philip II of Spain]], and the Holy Roman Empire to his brother, Ferdinand. Charles retired to the monastery of [[Yuste]] ([[Extremadura]], Spain), where he is thought to have had a [[nervous breakdown]], and died in 1558.