It is well accepted that unopposed estrogens increase the risk of developing endometrial cancer. A relationship between estrogen exposure and the risk for breast cancer is very probable. In addition, an association of long-term estrogen substitution and ovarian cancer risk has been postulated recently. Estrogens have been considered as typical tumor promotors. Due to their estrogen-receptor-mediated mitogenic activity, these steroids were supposed to increase the statistical probability of spontaneous mutations. Recent experimental findings, however, suggest that estrogen metabolites, in particular 4-hydroxyestrogens are capable of inducing DNA-damage and transforming mutations. The clinical relevance of these genotoxic properties of estrogens remains to be established, but could obtain great importance. First molecular-epidemiologic studies suggest that due to the specific activity of their estrogen metabolizing enzymes some women might produce relevant amounts of mutagenic estrogen metabolites, increasing their risk for breast-, endometrial- or ovarian cancer respectively. These findings might result in novel preventive strategies. The present data do not justify to abandon the practice of hormone replacement therapy with estrogens or estrogens plus progestins in non hysterectomised women. It seems to be wise, however, to restrict hormone replacement therapy to symptomatic women with a clear indication and, according to the actual trend, limit it temporarily.