Estrogen and progesterone play a critical role in normal and neoplastic development of the mammary gland. A long duration of estrogen and progesterone exposure is associated with increased breast cancer risk, and a short duration of the same doses of these hormones is associated with a reduced breast cancer risk. The protective effects of estrogen and progesterone have been extensively studied in animal models. Several studies have demonstrated that these hormones induce persistent and long-lasting alterations in gene expression in the mammary epithelial cells. In the experiments discussed herein, the protective effect of estrogen and progesterone is shown to occur in genetically engineered mice (the p53-null mammary gland). The protective effect is associated with a decrease in cell proliferation. The effects of hormones seem to manifest as a delay in premalignant progression. In the nontumor-bearing glands of hormone-treated mice, premalignant foci are present at the time the control glands are actively developing mammary tumors. If the hormone-treated cells are transplanted from the treated host to the untreated host, the cells resume their predetermined tumorigenic potential. The protective effect reflects both host-mediated factors (either stroma-determined or systemic factors) and mammary epithelial intrinsic changes. If normal, untreated p53 cells are transplanted into a host that has been previously treated with a short dose of hormones, the cells exhibit a significant delay in tumorigenesis. The relative contributions of host-mediated factors and mammary cell intrinsic factors remain to be determined. Current studies are moving this research area from the biological to the molecular realm and from the rodent models to human studies and offer the potential for directing prevention efforts at specific molecular targets.