The incidence of osteoporosis and of cardiovascular disease increases in women after menopause. Although theses diseases can be prevented by estrogen replacement therapy, this treatment is associated with an increased risk of endometrial cancer and perhaps also with an increased risk of breast cancer. Thus, a therapy that could prevent postmenopausal bone loss and lower serum cholesterol concentrations without stimulating reproductive tissues would be desirable. Selective estrogen receptor modulators (SERMs), such as raloxifene and tamoxifen, produce beneficial estrogen-like effects on bone and lipid metabolism, while antagonizing estrogen in reproductive tissue. Both agonist and antagonist activities are mediated via high affinity interaction with the estrogen receptor (ER). Both types of ER (alpha and beta) may be involved in the mechanism by which SERMs produce tissue-selective pharmacology. This review will discuss the roles of ER alpha and ER beta in novel signal transduction pathways.