In the Hands of Strangers is a collection of sixty-seven documents by writers and witnesses from the past, both black and white, that offer perspectives on the trade and movement of slaves. Many elucidate the long-standing discord between North and South over the issue of slavery.

Documents are divided into three parts that cover the African slave trade, the internal U.S. slave trade, and the series of conflicts and crises that led to the Civil War. They cover a variety of topics including the forced transport of slaves throughout East Coast and Gulf Coast states, buying and selling of slaves, increasingly contentious debates over the legitimacy of slavery, and effects of the breakup of families. The volume concludes with a brilliant essay by Frederick Douglass that asks the question: "What shall be done with the Negro?"