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The immune systems of post-pubescent males and females differ significantly with profound consequences to health and disease. In many cases, sex-specific differences in the immune responses of young adults are also apparent in aged men and women. Moreover, as in young adults, aged women develop several late-adult onset autoimmune conditions more frequently than do men, while aged men continue to develop many cancers to a greater extent than aged women. However, sex differences in the immune systems of aged individuals have not been extensively investigated and data addressing the effectiveness of vaccinations and immunotherapies in aged men and women are scarce. In this review, we evaluate age- and sex hormone-related changes to innate and adaptive immunity, with consideration about how this impacts age- and sex-associated changes in the incidence and pathogenesis of autoimmunity and cancer as well as the efficacy of vaccination and cancer immunotherapy. We conclude that future preclinical and clinical studies should consider age and sex to better understand the ways in which these characteristics intersect with immune function and the resulting consequences for autoimmunity, cancer, and therapeutic interventions.