Women are distinct from men in that females have a limited reproductive lifespan with a concomitant limit to the supply of gonadal estrogen and progesterone hormones. The reduction in endogenous estrogen levels causes the vasomotor symptoms of menopause, which can be disruptive to women’s lives and prompts many women to seek medical attention. Moreover, the shift from premenopause to menopause has diverse and profound effects on female physiology that is not limited to vasomotor symptoms. Menopausal hormone therapy (HT) was developed to treat these vasomotor symptoms of menopause, and to this day, estrogen remains the most effective treatment option. However, for the other age-related comorbidities associated with menopause, there remains controversy over whether HT has beneficial effects on these outcomes. Cardiovascular disease risk, for example, changes drastically with the menopause transition, with its manifestation rare prior to menopause and increasingly common afterward. As cardiovascular disease remains the leading cause of death in women in the United States, there remains much interest in preventive measures to reduce this risk. Although HT has been extensively investigated in this context, including several randomized controlled trials, it remains a contentious topic. The emerging consensus, however, is that HT is appropriate for treating bothersome menopausal symptoms, especially in early menopause, but findings do not support its routine use for prevention of cardiovascular disease or other chronic diseases. Transdermal estrogens in particular are preferred for management of menopausal symptoms in women at elevated risk for cardiovascular disease or who are obese, as the transdermal route avoids first-pass hepatic metabolism. Special populations who may benefit from HT for disease prevention, such as women with premature menopause, warrant separate consideration.