Multiple lines of evidence suggest that estrogen directly modulates angiogenesis via effects on endothelial cells. Under physiological conditions, angiogenesis is routinely observed in the uterus in association with fluctuations in the levels of circulating estradiol and other sex steroids. In pathological circumstances, such as breast cancer, a clear association between estrogen, estrogen receptor expression by endothelial cells, angiogenic activity, and/or tumor invasiveness has been made. Studies performed in our laboratory have revealed that estradiol accelerates functional endothelial recovery after arterial injury. Despite these consistent observations, the mechanisms by which estrogen regulates angiogenesis under physiological and pathological circumstances have not been defined.