For decades, hormone-replacement therapy (HRT) was considered safe and was the first choice in prevention of postmenopausal osteoporosis induced by estrogen deficiency. Numerous experimental and epidemiological studies further supported a protective effect of exogenous female sex hormones on atherogenesis and coronary heart disease (CHD) in women after the menopause. However, the fact that these promising results were not translated into lower incidences of CHD events in hormone-treated women compared with placebo in subsequent, large, randomized studies of healthy subjects as well as women with known CHD raised a very intense debate concerning the safety of HRT in terms of cardiovascular risk. A critical mass of data points toward a protective influence of HRT on cardiovascular disease end points in early postmenopausal women, but increased harm in elderly women, especially those with abdominal adiposity or metabolic syndrome. Once the quasi-hysterical reaction to the largest of the randomized studies (the Women's Health Initiative) has abated, a future strategy should be to concentrate on identifying those relatively few individuals who are not suitable for HRT, as HRT still remains the most thoroughly investigated pharmacological prevention strategy of osteoporosis.