In 1441 the expeditions began again using a new type of ship. Prince Henry's chamberlain, Antão Gonçalves, led an expedition to acquire a cargo of seal skins and oil with orders to go further into the unknown. On one occasion Gonçalves sought out a village along the Rio do Ouro and took several captives back to Portugal. This was the beginning of what would become the African Slave Trade. Another one of Henry's captains, Nuno Tristão, would discover the Bay of Arguim. Here Henry had a fort constructed in 1448 that would become the centre of trade with the African states of the interior. Tristão also found the end to the desert and reported the beginning of a lush green country. This inspired Dinis Dias raised enough capital to have Prince Henry grant him a license and a caravel. He sailed pass the Senegal River eventually arriving at the Cape of Verde that was the western limits of the African continent.

Not all the expeditions succeeded. Nuno Tristão died after being attacked with poison arrows by the inhabitants of a village he and his men were attempting to raid for slaves, leaving only five survivors to return home. Despite Tristão's death the voyages continued thanks to the rewards offered by the Regent Pedro and Prince Henry who recognised the potential of the African trade. Merchants like Fernão Gomes shared this vision and actively financed their own expeditions. In Gomes' case he petitioned the Crown for the exclusive rights to handle the trade of West Africa since the Crown was distracted by the Castilian war of succession that brought Isabella and Ferdinand to the Spanish throne. Gomes' ventures quickly grew into a thriving pepper trade that in turn led to his sailors' discovery of the gold-producing region of the Gold Coast (modern Ghana). When King João II (John II) succeeded his father, King Afonso V, to the throne of Portugal, he renewed the Crown's support of overseas exploration that had fallen by the wayside of his father's administration. Within four years King João II had personally sponsored, rather than simply granting a license, three expeditions led by Diogo Cão and Bartolomeu Dias that accomplished more in four years than his predecessors had in forty. These voyages reflected the change in policy from simply expanding overseas trade to finding a specific sea route to India.

In 1482 King João II sent out Diogo Cão on the first of two voyages. He discovered that the African continent turned south and ran for thousands more kilometres before eventually turning. Cão came to the Kingdom of the Congo where he began a trading relationship that would recoup the cost of the voyages. Bartolomeu Dias continued this exploration by rounding the southern extremity of the African continent in 1488, naming it the Cape of Good Hope. In 1484 King João II had rejected the proposals of Christopher Columbus who then sought out the patronage of Queen Isabella of Spain. With Columbus' discovery of the Caribbean and America, Isabella immediately requested that Pope Alexander VI endorse a series of bulls that divided the world into two parts by a line drawn from north to south one hundred leagues west of the Azores. King João II rejected this location of this line and opened negotiations with Spain immediately, the result was the Treaty of Tordesilla of 1494. Pope Alexander's line was moved to 370 leagues west of the Cape Verde Islands.