There is a strong link between menopause and increased cardiovascular disease incidence in women, and observational studies suggest that postmenopausal hormone replacement therapy (HRT) reduces cardiovascular disease risk. However, the only published prospective controlled trial of the effects of HRT on cardiovascular outcomes (Heart and Estrogen-Progestin Replacement Study, HERS) showed no net benefit of conventional HRT in women with established coronary disease. An angiograpic study of HRT in a similar patient population showed no regression of established coronary lesions in the active treatment group. Fundamental mechanistic studies of the cellular and molecular events by which hormones protect (or fail to protect) blood vessels are needed to define the role of postmenopausal HRT in cardiovascular disease. Herein, we review studies from our laboratory using the rat carotid injury model showing that estrogen inhibits neointima formation through an estrogen receptor (ER)-dependent mechanism operative in the early period after vascular injury. We have demonstrated that activation of vascular smooth muscle cells and subsequent release of soluble factors including osteopontin stimulate the migration of adventitial fibroblasts in a luminal direction to eventually take up residence in the neointima, and furthermore, that production, release, or posttranslational processing of these factors are inhibited by estrogen through an ER-dependent mechanism. The relevant observational and prospective data on HRT in cardiovascular disease prevention are reviewed, and the cardiovascular effects of estrogen are discussed.