The article looks at the relationship between the Papacy and Spain during the latter part of Ferdinand the Catholic's reign and assesses how it was impacted by the dinastic change that occurred with Charles of Hapsburg's ascension to throne. Important continuities are identified as well as extraordinary new developments like the protestant schism and the imperial election of Charles V, events that dramatized and reshaped this relationship. In this interplay between continuity and change the article focuses on the key and exceptional importance of territorial configurations of Italian peninsula.