The trafficking of African slaves to Spanish America remains largely unknown today in comparison with the trade in goods and merchandise that developed between Spain and its American colonies through the Carrera de Indias, or the slave trafficking systems set up by other Atlantic empires. This chapter traces the main lines of the political economy of the African slave trade to Spanish America and its specific characteristics as a commercial endeavor. Three elements characterized the slave trade in comparison to the regular Atlantic trade in goods and merchandise to Spanish America through the Carrera de Indias system. First, the routes that supplied slaves to Spanish America were of a trans-imperial nature. Second, the merchant networks controlling this infamous trade had a strong transnational component. Third, the shipping of slaves was highly decentralized with respect to Spain. A focus on these three aspects should help us better understand the various distribution mechanisms set up in the “New World” for the introduction of enslaved African people. With the Isthmus of Panama as its main geographic reference, this chapter concentrates on the period that runs from the early sixteenth century to the mid-seventeenth century and which represents the golden age of the Iberian empires’ slave trade in the Atlantic.