He managed the administration of a number of significant Spanish expeditions including voyages by Christopher Columbus and Magellan's circumnavigation of the earth.

He also took the leading role in the evolving Council of the Indies (formally established in 1524), which in time became the most influential royal institution governing the new settlements.

Upon the death of Queen Isabella in 1504, an aging King Ferdinand allowed Fonseca almost unlimited scope in administering the overseas colonies.

[2] Rodríguez de Fonseca was successively named Bishop of Badajoz (1495), of Córdoba (1499), of Palencia (1504), and, finally, of Burgos (1514), one of Castile’s wealthiest dioceses.

In 1513 King Ferdinand had asked the pope to elevate Rodríguez to a new title, that of Patriarch of the West Indies, a position that would bring a cardinal’s red hat.

Over his long career, Rodríguez de Fonseca inevitably made many enemies, most notably the Dominican bishop, Bartolomé de las Casas, known as the Protector of the Indians, who denounced him for his indifference to the cruelties that Spanish settlers inflicted on the native population of the new lands: when told that 7,000 children had been slaughtered in Cuba in three months, he is said to have retorted "and how does that concern me?