Why does hormone replacement therapy (HRT) with estrogens plus progestins increase the risk of breast cancer? First, experimental estrogen receptor-positive (ER+) and progesterone receptor-positive (PR+) human breast cancers contain a rare subpopulation of ER(-), PR(-) cancer stem cells. Especially in small, nascent ER+, PR+ tumor colonies, progestins, but not estrogens, reactivate cells with ER(-), PR(-) stem-like properties. Second, there is a reservoir of occult, undetected, preinvasive breast cancer in some women who are candidates for HRT. We propose that women who develop breast cancer while on estrogens plus progestins harbor undiagnosed nascent disease before the start of therapy. The progestin component, in a nonproliferative step, reactivates receptor-negative cancer stem cells within such germinal, perhaps even dormant tumors. After reacquiring receptors, these tumor cells are expanded by the mitogenic properties of estrogens. We argue that screening methods need to be improved to detect small, preexisting malignancies prior to the start of HRT. Women harboring such disease should be excluded from regimens that include systemic progestins.