Sex/gender significantly contribute to shape the immune responses, contributing to differences in the pathogenesis of infectious diseases in males and females, the response to viral vaccines and the prevalence of autoimmune diseases. Females typically develop higher innate, humoral and cellular immune responses to viral infections and in response to vaccine. At the same time, women are more prone to autoimmune diseases and experience more adverse reactions to vaccination. Hormonal, genetic and environmental factors between males and females may affect the immune responses and the sex-related outcome of vaccination. Knowledge of the mechanisms involved in sex disparity in immune responses will contribute to identify the ways to reduce adverse reactions in females and to improve the immune responses in males. This is necessary to adequately protect both sexes against the immune-mediated and infectious diseases with the long-term goal of personalizing the therapies for males and females.