There is a strong link between menopause and increased cardiovascular disease incidence in women, and observational studies suggest that postmenopausal hormone replacement therapy reduces cardiovascular disease risk by about half. Observational studies suffer from important limitations, however, and the only published prospective controlled trial of the effects of hormone replacement therapy on cardiovascular outcomes, the Heart Estrogen-Progestin Replacement Study (HERS), showed no net benefit of continuous estrogen plus synthetic progestin treatment in women with established coronary disease. Fundamental mechanistic studies of the cellular and molecular events by which hormones protect (or fail to protect) blood vessels from damage are needed to define the role of postmenopausal hormone replacement therapy in cardiovascular disease prevention. Most studies suggest that estrogen inhibits the neointimal response to acute injury in normal blood vessels, but this vasoprotective effect was not seen in vessels with preexisting atherosclerosis. Studies from our laboratory in the rat carotid injury model have shown that estrogen inhibits neointima formation via effects on all 3 layers of the vascular wall, including inhibition of medial smooth muscle cell migration and proliferation, stimulation of regrowth of endothelium, and inhibition of adventitial cell migration into neointima. Our laboratory is currently using transduced (lacZ) syngeneic fibroblasts as 'reporter' cells to delineate the factors that stimulate migration of adventitial cells into neointima after vascular injury and their modulation by estrogen and the other sex hormones. These fundamental studies will establish more rational strategies for therapeutic intervention in vascular diseases, including the basis for future gene therapy.