Hormone therapy was considered the standard of care before the publication of the Women's Health Initiative. After the study was published, the use of systemic hormone therapy dramatically decreased resulting in an increased incidence of menopausal symptoms such as hot flashes, vaginal dryness, and dyspareunia experienced by women. Use of vaginal estrogen offers women a unique alternative for relief of these symptoms. This article reviews the systemic effects of vaginally administered estrogen. Effects on serum hormone levels, vasomotor symptoms, lipid profiles, and use in women with breast cancer are reviewed. An accompanying review (J Pelvic Med Surg. 2009;15:105-114.) examines the local effects of vaginally administered estrogen. Copyright © 2010 by Lippincott Williams & Wilkins.