Significance Following an acute viral infection, the majority of activated virus-specific CD8 T cells die off, while a smaller subset survives and develops into long-lived memory CD8 T cells. The underlying process regulation of this cell fate decision remains incompletely understood. In this study, we identify two main patterns of gene regulatory networks underlying effector and memory CD8 T cell differentiation. Furthermore, enhancer activity correlates with these regulon patterns. Finally, cells destined to become memory CD8 T cells maintain accessibility at enhancers regulating key memory-related genes, and the transcription factor E2A regulates the accessibility of many memory-related enhancers to promote memory cell formation.