Germinal centers (GCs) are key microanatomical sites in lymphoid organs where responding B cells mature and undergo affinity-based selection. The duration of the GC reaction has long been assumed to be relatively brief, but recent studies in humans, nonhuman primates, and mice indicate that GCs can last for weeks to months after initial antigen exposure. This review examines recent studies investigating the factors that influence GC duration, including antigen persistence, T-follicular helper cells, and mode of immunization. Potential mechanisms for how persistent GCs influence the B-cell repertoire are considered. Overall, these studies provide a blueprint for how to design better vaccines that elicit persistent GC responses.