Endogenous estrogen exposure has long been implicated in the causation of breast cancer through a mechanism of epithelial cell proliferation. Whether estrogen, progesterone, or both exhibit mitogenic activity and promote carcinogenesis in the human breast has been the subject of considerable debate. The purpose of this review article is to examine the evidence for the effects of hormone replacement therapy in its various forms on the biology of the postmenopausal breast both in humans and in an animal model, and to identify the gaps in knowledge that research will need to address to further understand this complex issue.