CD4 memory T cells play a critical role in protection against repeated exposure to infectious agents such as viruses, bacteria, and helminth parasites, yet can also contribute to the aberrant immune responses associated with autoimmune and allergic reactions. Understanding the mechanisms that control effective memory responses has important ramifications for vaccine design and in the management of adverse immune reactions. Recent advances in studies of T cell memory have implicated the tumor-necrosis-factor receptor (TNFR) family member, OX40 (CD134), as a key co-stimulatory molecule involved in the regulation of CD4 memory T cells. In this review we discuss these new developments in the context of past research and current models for the generation, persistence, and re-activation of memory T cells.