Oxidative metabolism of the estrogens estrone (E1) and estradiol (E2) is the critical event in the initiation of cancer by estrogens. E1 and E2 are oxidized by cytochrome P450 (CYP) to the catechol estrogens 2-OHE1(E2) and 4-OHE1(E2) and then to the catechol estrogen quinones, which react with DNA to form estrogen-DNA adducts. The E1(E2)-3,4-quinones [E1(E2)-3,4-Q] react predominantly with DNA to form the depurinating adducts 4-OHE1(E2)-1-N3Ade and 4-OHE1(E2)-1-N7Gua. Loss of these adducts forms apurinic sites in the DNA that can generate mutations leading to the initiation of cancer. When estrogen metabolism becomes unbalanced toward oxidation, larger amounts of adducts are formed, and the risk of initiating cancer is greater. Women at high risk of developing breast cancer, or diagnosed with the disease, have higher levels of estrogen-DNA adducts than women at normal risk. With unbalanced estrogen metabolism, women are six-times more likely to be diagnosed with ovarian cancer. These results and others in humans and cell culture indicate that unbalanced oxidative metabolism of estrogens with formation of estrogen-DNA adducts is a critical event in the initiation of cancer. Two compounds, N-acetylcysteine and resveratrol, efficiently block formation of estrogen-DNA adducts and, thus, are promising agents to prevent cancer.