The steroid hormone, progesterone (P), is a central coordinator of all aspects of female reproductive activity and plays a key role in pregnancy-associated mammary gland morphogenesis and mammary tumorigenesis. The effects of P on the mammary gland are mediated by two structurally and functionally distinct nuclear receptors PR-A and PR-B that arise from a single gene. Null mutation of both receptors in PR knockout (PRKO) mice has demonstrated a critical role for PRs in mediating pregnancy-associated mammary ductal branching and lobuloalveolar differentiation and in initiation of mammary tumors in response to carcinogen. Analysis of the molecular genetic pathways disrupted in PRKO mice has recently yielded important insights into the molecular mechanisms of regulation of mammary gland morphogenesis by PRs. In addition to its essential role in regulating proliferative and differentiative responses of the adult mammary gland during pregnancy, P plays a critical role in the protection against mammary tumorigenesis afforded by early parity. Thus, the effects of P on postnatal developmental plasticity of the mammary gland differ between young and adult glands. This review will summarize recent advances in our understanding of 1) the molecular mechanisms by which PRs mediate pregnancy-associated mammary gland morphogenesis, 2) the role of PRs in mediating tumorigenic responses of the adult mammary gland to carcinogen, and 3) the role of P in long-term protection of the juvenile mammary gland against tumorigenesis. In addition, we will summarize recent insights into the isoform selective contributions to some of these activities of PRs obtained from comparative analysis of P-dependent mammary gland development in PR isoform specific knockout mice lacking either the PR-A (PRAKO) or PR-B (PRBKO).