Reproductive history is a consistent risk factor for human breast cancer. Epidemiological studies have repeatedly demonstrated that early age of first full-term pregnancy is a strong protective factor against breast cancer and provides a physiologically operative model to achieve a practical mode of prevention. In rodents, the effects of full-term pregnancy can be mimicked by exposure to low doses of estrogen and progesterone or treatment with human chorionic gonadotropin. The cellular and molecular mechanisms that underlie hormone-induced refractoriness are largely unresolved. Several hypotheses have been proposed to explain the protective effects of hormones. These involve the induction of differentiation of the mammary gland to provide a less responsive cell population to carcinogens, a decrease in proliferative activity in the parous gland compared to the age-matched virgin, an altered hormonal environment mediated by a decrease in circulating growth hormone, and an alteration in cell fate mediated by specific molecular changes induced by estrogen and progesterone. The evidence for and against these hypotheses is discussed along with recent results on possible molecular alterations that may underlie the refractory state. One central question that is still unresolved is whether the refractoriness is intrinsic to the mammary epithelial cells and/or mediated by persistent alterations in the host environment.