The female predominance of polyarticular osteoarthritis (OA), and in particular the marked increase of OA in women after the menopause points to a likely involvement of female sex hormones in the maintenance of cartilage homeostasis. This perception has inspired many research groups to investigate the role of estrogens in the modulation of cartilage homeostasis with the ultimate aim to clarify whether estrogen replacement therapy (ERT) could provide benefits in preventing the rapid rise in the prevalence of OA in postmenopausal women. The effects of ERT and selective estrogen-receptor modulators on the joint in various experimental models have been investigated. Clinically, the effects of estrogens have been evaluated by post hoc analysis in clinical trials using biochemical markers of cartilage and bone degradation. Lastly, the Women's Health Initiative trial (WHI) investigated the effects of estrogens on the joint and joint replacements. Even though the exact mode of action still needs to be elucidated, the effect involves both direct and indirect mechanisms on the whole joint pathophysiology. Several animal models have demonstrated structural benefits of estrogens, as well as significant effects on joint inflammation. This is in complete alignment with clinical data using biochemical markers of joint degradation which demonstrated approximately 50% inhibition of cartilage destruction. These finding were recently validated in WHI, where women taking estrogens had significantly less joint replacement. In conclusion, the pleiotropic effect of estrogens on several different tissues may match the complicated aetiology of OA in some important aspects