Why does hormone replacement therapy (HRT) with estrogens (E) plus progestins (P) increase the risk of breast cancer? First, experimental estrogen receptor (ER+) and progesterone receptor (PR+) positive 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, pre-invasive breast cancer in many women who are candidates for HRT. We propose that women who "develop" breast cancer while on E+P harbor undiagnosed nascent disease before the start of therapy. The progestin component, in a non-proliferative step, reactivates receptor-negative cancer stem cells within such germinal, perhaps even dormant tumors. After re-acquiring receptors, these tumor cells are expanded by the mitogenic properties of estrogens. We argue that screening methods need to be improved to detect small, pre-existing malignancies prior to the start of HRT. Women harboring such disease should be excluded from regimens that include systemic progestins.