The higher incidence of cardiovascular disease in men than in women of similar age, and the menopause-associated increase in cardiovascular disease in women, has led to speculation that gender-related differences in sex hormones have a key role in the development and evolution of cardiovascular disease. Compelling data have indicated that sex differences in vascular biology are determined not only by gender-related differences in sex steroid levels, but also by gender-specific tissue and cellular differences that mediate sex-specific responses. In this Review, we describe the sex-specific effects of estrogen and testosterone on cardiovascular risk, direct vascular effects of these sex hormones, and how these effects influence development of atherosclerosis. Cardiovascular effects of exogenous hormone administration are also discussed. Importantly, evidence has indicated that estrogens alone or in combination with progestins in postmenopausal women increase cardiovascular risk if started late after menopause, but that it possibly has beneficial cardiovascular effects in younger postmenopausal women, although data on long-term testosterone therapy are lacking. Hormone therapy should not be considered solely for primary prevention or treatment of cardiovascular disease at this time.