Heart disease presentation can differ between the sexes because nonobstructive coronary disease and angina unrelated to exercise are considerably more prevalent in women than in men. When the outcomes of large, randomized, controlled trials failed to demonstrate cardiac risk protection, many women and their physicians abandoned hormone replacement therapy as primary or secondary prevention for cardiovascular disease. We are concerned that the apparent blanket condemnation of steroids has not sufficiently distinguished between the cardiovascular actions of estrogen, progesterone and the synthetic progestin medroxyprogesterone acetate. The actions of active metabolites of progestins are not well understood and in some cases have not been explored. We intend to present what is known and what is not known about progesterone per se versus medroxyprogesterone acetate, particularly with regard to cardiovascular effects. This Review considers the mounting evidence that progesterone improves cardiovascular function and proposes its mechanism of action-restoration of a threshold level of progesterone as preventive of microvascular cardiac ischemia-and compares oral and transdermal routes of administration. We hope to stimulate research to determine whether progesterone, with or without estrogen, has a role in reducing cardiovascular risk and treating cardiovascular disease including myocardial ischemia in postmenopausal women.