Although discovered in 1446 by the Portuguese navigator Nuno Tristão, this part of the Guinea coast was virtually forgotton until the need for slaves to work the mines and plantations in Portuguese Brazil became apparent.
The expansion of the Mande peoples southwards caused intertribal warfare that increased the number of prisoners available for export as slaves.

A trading and slave port was established at Cacheu by traders from Cape Verde in 1614 that was at times successful when supported by the government of Portugal. In 1687 another port was established at Bissau in an attempt to limit French expansion but folded a few years later. The abortive British attempt in 1792 to claim the island and settlement of Bolama as part of Sierra Leone, was resolved in favour of the Portuguese in 1830.

The three reestablished Portuguese settlements of Bissau, Cacheu and Bolama were administered from Cape Verde Islands, but in 1879 was made a separate colony with Bolama as seat of administration. The Portuguese conquest of the interior did not begin until the latter half of the 19th century and ended with the conquest of the Bijagos Islands in 1936.