The pathophysiologies of osteoporosis, cardiovascular disease, and breast cancer are briefly reviewed within the context of the relevance and safety of long-term estrogen therapy (ET). Extrapolation of data from the known underlying biology of these diseases and the results of randomized controlled clinical trials suggest that selective ET is appropriate and safe for the majority of postmenopausal women. A key element to this clinical practice is individualization of ET, which includes timing of the initiation of therapy, selection of the route and possibly the type of estrogen prescribed, adjustment of the dose of estrogen over time to compensate for local tissue estrogen synthesis, and annual monitoring and reassessment of the indication for continuing therapy. Established disease requires disease-specific therapy but does not exclude ET cotherapy provided there is an indication for its use. Estrogen-dependent cancer is an absolute contraindication to systemic ET.