For Charles V and Philip II, both of whom expected to continue the momentum of the Reconquista into a campaign against Islam, the theology and political successes of Martin Luther and John Calvin menaced not just the possibility of a universal empire, but the survival of the Habsburg monarchy. Moreover, the Protestant Reformation stimulated changes within Spain and other Habsburg domains, reinvigorating the Spanish Inquisition against new enemies, reinforcing Catholic orthodoxy, and restricting the reach of the Renaissance and Scientific Revolution. This book argues that the Protestant Reformation was an existential threat to the Catholic Habsburg monarchy of the sixteenth century and the greatest danger to its political and religious authority in Europe and the world. Spain’s war on the Reformation was a war for the future of Europe, in which the Spanish Inquisition was the most effective weapon. This war, led by Charles V and Philip II was in the end a triumphant failure: Spain remained Catholic, but its enemies embraced Protestantism in an enduring way, even as Spain’s vision for a global monarchy faced military, political, and economic defeats in Europe and the broader world. Spain and the Protestant Reformation will appeal to researchers and students alike interested in the history and society of Early Modern Spain.