A greater understanding of the molecular biology of estrogen receptor (ER) will allow the extension of its utility as a target in therapy to an increased number of patients. The treatment of ER-positive breast cancer with antiestrogens involves a very sophisticated decision. Patients are treated with tamoxifen based on the direct measurement of the level of ER expression in the tumor and an indirect assessment of its activity through the measurement of an important target gene, progesterone receptor (PR). An understanding of the mixed agonist-antagonist nature of tamoxifen has led to the development of pure antagonists with clinical potential. Thus, the hormonal therapy of breast cancer can serve as the paradigm for the rational treatment of cancer based on the presence of the specific target of the therapy in the tumor and an understanding at the molecular level of the function of that target.