Sexual dimorphism or sex bias in diseases and mental disorders have two biological causes: sexual selection and sex hormones. We review the role of sexual selection theory and bring together decades of molecular studies on the variation and evolution of sex-biased genes and provide a theoretical basis for the causes of sex bias in disease and health. We present a
Sexual Selection-Sex Hormonetheory and show that male-driven evolution, including sexual selection, leads to: (1) increased male vulnerability due to negative pleiotropic effects associated with male-driven sexual selection and evolution; (2) increased rates of male-driven mutations and epimutations in response to early fitness gains and at the cost of late fitness; and (3) enhanced female immunity due to antagonistic responses to mutations that are beneficial to males but harmful to females, reducing female vulnerability to diseases and increasing the thresholds for disorders such as autism. Female-driven evolution, such as reproduction-related fluctuation in female sex hormones in association with stress and social condition, has been shown to be associated with increased risk of certain mental disorders such as major depression disorder in women. Bodies have history, cells have memories. An evolutionary framework, such as the Sexual Selection–Sex Hormonetheory, provides a historical perspective for understanding howthe differences in the sex-biased diseases and mental disorders have evolved over time. It has the potential to direct the development of novel preventive and treatment strategies.