The steroid hormone, progesterone, plays a central coordinate role in diverse events associated with female reproduction. In humans and other vertebrates, the biological activity of progesterone is mediated by modulation of the transcriptional activity of two progesterone receptors, PR-A and PR-B. These receptors arise from the same gene and exhibit both overlapping and distinct transcriptional activities in vitro. To delineate the individual roles of PR-A and PR-B in vivo, we have generated mouse models in which expression of a single PR isoform has been ablated. Analysis of the reproductive phenotypes of these mice has indicated that PR-A and PR-B mediate mostly distinct but partially overlapping reproductive responses to progesterone. While selective ablation of the PR-A protein (PR-A knockout mice, PRAKO mice) shows normal mammary gland response to progesterone but severe uterine hyperplasia and ovarian abnormalities, ablation of PR-B protein (PRBKO mice) does not affect biological responses of the ovary or uterus to progesterone but results in reduced pregnancy-associated mammary gland morphogenesis. The distinct tissue-specific reproductive responses to progesterone exhibited by these isoforms are due to regulation of distinct subsets of progesterone-dependent target genes by the individual PR isoforms. This review will summarize our current understanding of the selective contribution of PR isoforms to the cellular and molecular actions of progesterone in reproductive tissues.