Africa’s arbitrary country borders have been seized upon as sources of “natural experiments”: having randomly assigned people to different country treatments, differences in outcomes on either side of the border can then be attributed to the institutions, demographics, or policies put in place in each country. While methodologically attractive, the use of African borders as sources of natural experiments presents several potential pitfalls. We describe these pitfalls—some common to all studies that employ jurisdictional boundaries, some unique to African borders—and offer guidelines for overcoming them. We conclude that African cross-border studies can provide research advantages similar to well-executed comparative case studies, but that they frequently offer weaker inferential leverage than is claimed.