An estimated one third of postmenopausal women in the United States use hormone replacement therapy (HRT) to treat symptoms of menopause and prevent chronic conditions. In the context of this widespread use, evidence has been growing about the potential harms of HRT, particularly regarding long-term use. Physicians and patients are often confused about how to use results of studies in individual cases. This article applies the current state of evidence for the benefits and harms of HRT to management decisions in 4 clinical situations. Patient preferences, as well as evidence, are important for these decisions. Benefits and harms need to be readdressed periodically to apply newly published evidence and to reassess emerging risks, comorbidities, and needs of individuals.