Estrogens are eliminated from the body by metabolic conversion to estrogenically inactive metabolites that are excreted in the urine and/or feces. The first step in the metabolism of estrogens is the hydroxylation catalyzed by cytochrome P450 (CYP) enzymes. Since most CYP isoforms are abundantly expressed in liver, the metabolism of estrogens mainly occurs in the liver. A major metabolite of estradiol, 2-hydroxyestradiol, is mainly catalyzed by CYP1A2 and CYP3A4 in liver, and by CYP1A1 in extrahepatic tissues. However, CYP1B1 which is highly expressed in estrogen target tissues including mammary, ovary, and uterus, specifically catalyzes the 4-hydroxylation of estradiol. Since 4-hydroxyestradiol generates free radicals from the reductive-oxidative cycling with the corresponding semiquinone and quinone forms, which cause cellular damage, the specific and local formation of 4-hydroxyestradiol is important for breast and endometrial carcinogenesis. Changes in the expression level of estrogen-metabolizing CYP isoforms not only alter the intensity of the action of estrogen but may also alter the profile of its physiological effect in liver and target tissues. Generally, many CYP isoforms are induced by the substrates themselves, resulting in enhanced metabolism and elimination from the body. Of particular interest is a novel finding that human CYP1B1 is regulated by estradiol via the estrogen receptor. This fact suggests that the regulation of CYP enzymes involved in estrogen metabolism by estrogen itself would be physiologically significant for the homeostasis of estrogens at local organs. In this mini-review, we discuss the CYP-mediated metabolism of estrogens and the regulation of the estrogen-metabolizing CYP enzymes in relation to the risk of cancer.