The Woman's Health Initiative has conducted 2 full-scale, placebo-controlled clinical trials to determine the influence of menopausal therapy on breast cancer incidence and outcome. Estrogen plus progestin use in postmenopausal women with a uterus increases breast cancer incidence and deaths from breast cancer. Despite a short-term reduction in risk after stopping estrogen plus progestin use, an increase in breast cancer risk persists postintervention. Estrogen-alone use in postmenopausal women with prior hysterectomy reduces breast cancer incidence and reduces deaths from breast cancer. The reduced breast cancer risk persists for several years after stopping estrogen-alone use but is lost in late postintervention. These findings suggest recalibration of breast cancer risk and benefit consideration for both regimens, with estrogen plus progestin use associated with greater risk and estrogen-alone use associated with greater benefit. Use of either regimen in clinical practice requires careful consideration of all clinical risks and benefits.