A protective effect of estrogen is the most obvious reason for the substantial and consistent favored status of women vs. men with regard to coronary heart disease (CHD). This paper briefly reviews the history of studies of the estrogen-heart disease hypothesis, the reason why clinical trials of postmenopausal estrogen are necessary (despite the strength, consistency, and plausibility of the 'protection' seen in observational studies), and the status of the 'Postmenopausal Estrogen/Progestin Interventions' (PEPI) trial results and ongoing trials. The potential for nonhormonal primary prevention is emphasized.