The cardiovascular effects of hormone replacement therapy (HRT) have been the subject of much debate since the initial findings from the Women's Health Initiative (WHI) were reported. However, re-analyses of WHI results have suggested that the association between HRT use and cardiovascular risk is influenced by several factors and that, among these, age and time since menopause may play a key role. Preclinical and human studies have shown differential effects of estrogen on the vasculature of healthy subjects compared with those with existing atherosclerosis. Indeed, while HRT has shown no protective effects in the presence of established atherosclerotic disease, it may have beneficial or neutral effects on healthy vasculature or early atherosclerosis. However, the final cardiovascular effects of estrogens in non-hysterectomized women are influenced by the type, dosage, and route of administration of the progestin used in association. The results of ongoing studies on the timing of HRT initiation will help women make better informed decisions regarding their menopausal health. Current treatment guidelines recommend initiation of HRT in recently postmenopausal women for the relief of vasomotor symptoms.