Elderly humans are at significant risk with regard to the incidence and severity of many infectious diseases and cancers. Current theory holds that these late-life vulnerabilities arise, in part, through age-related changes in immune function, particularly in the T lymphocyte lineage. Herein, we discuss how such factors as thymic involution and ongoing T cell differentiation in the peripheral tissues contribute to progressive and irreversible shifts in the state of differentiation of the mature T cell pool. We propose that, by late life, these processes yield a T cell compartment with a suboptimal balance of naive and memory T cell subsets, each with altered, subset-specific programs for cytokine gene expression. As such, the T cell compartment in late life may be more prone to immune deficiency or cytokine-mediated dysregulation in response to new or previously encountered pathogens.