Biological sex and age have profound effects on immune responses throughout the lifespan and impact vaccine acceptance, responses, and outcomes. Mounting evidence from epidemiological, clinical, and animal model studies show that males and females respond differentially to vaccination throughout the lifespan. Within age groups, females tend to produce greater vaccine-induced immune responses than males, with sex differences apparent across all age groups, but are most pronounced among reproductive aged individuals. Females report more adverse effects following vaccination than males. Females, especially among children under 5 years of age, also experience more non-specific effects of vaccination. Despite these known sex- and age-specific differences in vaccine-induced immune responses and outcomes, sex and age are often ignored in vaccine research. Herein, we review the known sex differences in the immunogenicity, effectiveness, reactogenicity, and non-specific effects of vaccination over the lifespan. Ways in which these data can be leveraged to improve vaccine research are described.