Estrogens occurring naturally in the body are metabolized to catecholestrogens (2‐ and 4‐hydroxyestradiol) by the cytochrome P450 enzymes. 2‐Hydroxy catecholestrogens are further metabolized by catechol‐ O ‐methyltransferase to 2‐methoxyestradiol, which is known to be protective against tumor formation. 2‐Methoxyestradiol exhibits potent apoptotic activity against rapidly growing tumor cells. It also possesses antiangiogenic activity through a direct apoptotic effect on endothelial cells. Other molecular mechanisms, including microtubule stabilization by inhibition of the colchicine‐binding site, have been reported. The exact mechanism of action of 2‐methoxyestradiol is still unclear, but it has been shown to be effective in preventing tumor growth in a variety of cell lines. 2‐Methoxyestradiol also possesses cardioprotective activity by inhibiting vascular smooth muscle cell growth in arteries. It has a lower binding affinity for estrogen receptor α compared with that of estradiol, and its affinity for estrogen receptor β is even lower than that of estrogen receptor α, thus it has minimal estrogenic activity. 2‐Methoxyestradiol is distinct because of its inability to engage estrogen receptors as an agonist, and its unique antiproliferative and apoptotic activities are mediated independently of estrogen receptors α and β. A phase I clinical trial of 2‐methoxyestradiol 200, 400, 600, 800, and 1000 mg/day in 15 patients with breast cancer showed significant reduction in bone pain and analgesic intake in some patients, with no significant adverse effects. Another phase I study of 2‐methoxyestradiol 200–1000 mg/day in combination with docetaxel 35 mg/m 2 /week for 4–6 weeks performed in 15 patients with advanced refractory metastatic breast cancer showed no serious drug‐related adverse effects. A phase II randomized, double‐blind trial of 2‐methoxyestradiol 400 and 1200 mg/day in 33 patients with hormone‐refractory prostate cancer showed that it was well tolerated and showed prostate specific antigen stabilizations and declines. We have started a phase I clinical trial to explore dosages greater than 1000 mg/day.