Coronary artery disease (CAD) is still the most common killer of western women. Coronary arteries, expressing estrogen receptors, are a target for estrogen action. Prior to the Women's Health Initiative (WHI) study, postmenopausal hormone therapy (HT) was widely advocated for primary prevention of CAD, but such use was criticized after the WHI publication. However, new data accumulated in the USA and in Europe indicate that the use of estradiol-based HT regimens does not endanger the heart, but rather, it significantly reduces the incidence of CAD events and mortality. This effect may be related to the presence of hot flushes before HT initiation, because they may indicate a greater responsiveness of the cardiovascular system to HT. To get maximal cardioprotective efficacy of HT, a woman should initiate HT as soon as symptoms occur, and preferably within the first 10 postmenopausal years. Recent guidelines for optimal use of HT recommend pauses of HT at 1-2-year intervals to see whether hot flushes and other symptoms still persist. However, new data question the safety of this policy, because acute withdrawals of estradiol from the circulation may predispose to potentially fatal CAD events. All these data support modernized guidelines for optimal HT use.