Two crucial and interrelated elements of the Columbian exchange were the transatlantic trade in sugar and slaves. Throughout the Middle Ages, slavery was deeply entrenched in the Mediterranean, but it was not based on race; many slaves were European in origin. How, then, did black African slavery enter the European picture and take root in South and then North America? In 1453 the Ottoman capture of Constantinople halted the flow of European slaves from the eastern Mediterranean. Additionally, the successes of the Christian reconquest of the Iberian Peninsula drastically diminished the supply of Muslim captives. Cut off from its traditional sources of slaves, Mediterranean Europe turned to sub-Saharan Africa, which had a long history of slave trading.

As Portuguese explorers began their voyages along the western coast of Africa, one of the first commodities they sought was slaves. In 1444 the first ship returned to Lisbon with a cargo of enslaved Africans. While the first slaves were simply seized by small raiding parties, Portuguese merchants soon found that it was easier and more profitable to trade with African leaders, who were accustomed to dealing in enslaved people captured through warfare with neighboring powers. In 1483 the Portuguese established an alliance with the kingdom of Kongo. The royal family eventually converted to Christianity, and Portuguese merchants intermarried with Kongolese women, creating a permanent Afro-Portuguese community. From 1490 to 1530 Portuguese traders brought between three hundred and two thousand enslaved Africans to Lisbon each year. There they performed most of the manual labor and constituted 10 percent of the city's population.

In this stage of European expansion, the history of slavery became intertwined with the history of sugar. Originally sugar was an expensive luxury, but population increases and greater prosperity in the fifteenth century led to increasing demand. The establishment of sugar plantations on the Canary and Madeira Islands in the fifteenth century testifies to this demand.

Sugar was a particularly difficult crop to produce for profit. Seed-stems were planted by hand, thousands to the acre. When mature, the cane had to be harvested and processed rapidly to avoid spoiling. Moreover, sugarcane has a virtually constant growing season, meaning that there was no fallow period when workers could recuperate. The invention of roller mills to crush the cane more efficiently meant that yields could be significantly augmented, but only if a sufficient labor force was found to supply the mills. Europeans solved the labor problem by forcing first native islanders and then transported Africans to perform the backbreaking work.

The transatlantic slave trade that would ultimately result in the forced transport of over 12 million individuals began in 1518, when Spanish king Charles V authorized traders to bring enslaved Africans to New World colonies. The Portuguese brought the first slaves to Brazil around 1550; by 1600 four thousand were being imported annually. After its founding in 1621, the Dutch West India Company transported thousands of Africans to Brazil and the Caribbean, mostly to work on sugar plantations. In the late seventeenth century, with the chartering of the Royal African Company, the English began to bring slaves to Barbados and other English colonies in the Caribbean and mainland North America.

Before 1700, when slavers decided it was better business to improve conditions, some 20 percent of slaves died on the voyage from Africa to the Americas.10 The most common cause of death was dysentery induced by poor-quality food and water, lack of sanitation, and intense crowding. (To increase profits, slave traders packed several hundred captives on each ship.) Men were often kept in irons during the passage, while women and girls were subject to sexual abuse by sailors. On sugar plantations, death rates among enslaved people from illness and exhaustion were extremely high, leading to a constant stream of new human shipments from Africa. Driven by rising demands for sugar, cotton, tobacco, and other plantation crops, the tragic transatlantic slave trade reached its height in the eighteenth century.