CD8 memory T cells can play a critical role in protection against repeated exposure to infectious agents such as viruses, yet can also contribute to the immunopathology associated with these pathogens. Understanding the mechanisms that control effective memory responses has important ramifications for vaccine design and in the management of adverse immune reactions. Recent studies have implicated several members of the tumor necrosis factor receptor (TNFR) family as key stimulatory and inhibitory molecules involved in the regulation of CD8 T cells. In this review, we discuss their control of the generation, persistence, and reactivation of CD8 T cells during virus infection.