High-dose estrogen was generally considered the endocrine therapy of choice for postmenopausal women with breast cancer prior to the introduction of tamoxifen. Subsequently, the use of estrogen was largely abandoned. Recent clinical trial data have shown clinically meaningful efficacy for high-dose estrogen even in patients with extensive prior endocrine therapy. Preclinical research has demonstrated that the estrogen dose-response curve for breast cancer cells can be shifted by modification of the estrogen environment. Clinical and laboratory data together provide the basis for developing testable hypotheses of management strategies, with the potential of increasing the value of endocrine therapy in women with breast cancer.