Health and lifespan disparities between sexes are dependent on the immune responses. Men and women have different life styles which determine the environment, nutritional requirements and their interactions with the sex hormones. Sexual dimorphism in innate and adaptive immunity determines responses to infections and other environmental factors regulating health and diseases. Sex hormones regulate immune responses through the expression of receptors which differ for female and male hormones. Estrogen receptors are expressed in brain, lymphoid tissue cells and many immune cells while androgen receptors are limited in expression. Genetic, epigenetic factors and X chromosome linked immune function genes are important in enhanced adaptive immunity in females, leading to production of higher levels of antibodies compared to males. Different nutritional requirements and hormonal control of the mucosal microbiome and its function regulate mucosal immunity. Hormonal changes during various aspects of life and during aging control immune senescence. Evolutionarily, females have an advantage during young age when they are protected from infections by heightened immune reactivity though during aging that can lead to pathologies. Considering the sexual dimorphism in immunity, guidelines need to be established for sex-based treatments for optimal response.