Immune memory is critical for protection from repeated infections by pathogenic organisms and is the basis for the success of vaccines. Memory CD8+ T cell development is guided by important signals that alter their function and transcriptional program, enabling them to persist as pools of primed memory cells capable of rapid response. Lymphoid organs are highly innervated by sympathetic neurons that secrete norepinephrine as the primary neurotransmitter, which places the nervous and immune systems in direct communication. CD8+ T cells express the β2-adrenergic receptor (ADRB2), and we found that it was required for the development of long-lived memory cells in response to virus infection. The failure of Adrb2−/− T cells to form memory populations correlated with profound differences in gene expression and predicted upstream regulators during the early stages of T cell priming. Thus, the sympathetic nervous system controls memory CD8+ T cell development through ADRB2 signaling.