The association of female sex with certain rheumatic symptoms and diseases is now indisputable. Some of the most striking examples of this association occur in individuals with musculoskeletal pain and osteoarthritis, in whom sex-dependent changes in incidence and prevalence of disease are seen throughout the lifecourse. Joint and muscle pain are some of the most common symptoms of menopause, and there is increasingly compelling evidence that changes in or loss of sex hormones (be it natural, autoimmune, pharmacological, or surgical) influence musculoskeletal pain propensity and perhaps disease. However, the effects of modulation or replacement of sex hormones in this context are far less established, particularly whether these approaches could represent a preventative or therapeutic opportunity once symptoms have developed. In this Review, we present evidence for the association of changes in sex hormones with musculoskeletal pain and painful osteoarthritis, discussing data from diverse natural, therapeutic, and experimental settings in humans and relevant animal models relating to hormone loss or replacement and the consequent effects on health, pain, and disease. We also postulate mechanisms by which sex hormones could mediate these effects. Further research is needed; however, increased scientific understanding of this complex area could lead to real benefits in musculoskeletal and women's health.