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The first decades of Ferdinand and Isabella's joint rule were taken up with the conquest of the Kingdom of Granada, the last Muslim enclave in the Iberian peninsula, which was completed by 1492. In that same year, the Alhambra Decree was issued, expelling the Jews from both Castile and Aragon, and Christopher Columbus was sent by the couple on his infamously accidental expedition to the new world. By the Treaty of Tordesillas of 1494, the extra-European world was split between the crowns of Portugal and Castile by a north-south line through the Atlantic Ocean. Wedding portrait of King Ferdinand II of Aragón and Queen Isabella of Castile. The latter part of Ferdinand's life was largely taken up with disputes over control of Italy with successive Kings of France, the so-called Italian Wars. In 1494, Charles VIII of France invaded Italy and expelled Alfonso II (who was Ferdinand's first cousin once removed and stepson of Ferdinand's sister) from the throne of Naples. Ferdinand allied with various Italian princes and with Emperor Maximilian I, to expel the French by 1496 and install Alfonso's son, Ferdinand, on the Neapolitan throne. In 1501, following the death of Ferdinand II of Naples and his succession by his uncle Frederick, Ferdinand of Aragon signed an agreement with Charles VIII's successor, Louis XII, who had just successfully asserted his claims to the Duchy of Milan, to partition Naples between them, with Campania and the Abruzzi, including Naples itself, going to the French and Ferdinand taking Apulia and Calabria. The agreement soon fell apart, and over the next several years, Ferdinand's great general Gonzalo Fernández de Córdoba conquered Naples from the French, having succeeded by 1504. Another less famous "conquest" took place in 1503, when Andreas Paleologus, de jure Emperor of the Eastern Roman Empire, left Ferdinand and Isabella as heirs to the empire, thus Ferdinand became de jure Roman Emperor.

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