Apart from distinguishing the in vivo effects of progesterone (P) from those of estrogen (E), the progesterone receptor knockout (PRKO) mouse has furnished unprecedented access to novel cell-signaling paradigms, hitherto unsuspected. Along with providing new cellular principles by which P influences proliferative and differentiative programs obligate for tissue development and tumor progression, the PRKO in conjunction with transcript profiling has begun to uncover the transcriptional cascades underlying these processes. Moreover, studies on isoform-specific knockouts for PR-A (PR-AKO) and PR-B (PR-BKO) have clearly defined distinct physiological roles for the two subtypes of PR, providing essential physiological support for previous in vitro observations. Although the PR-AKO exhibits an infertility phenotype, the PR-BKO displays normal fecundity. Conversely, although normal mammary morphogenesis can manifest in the PR-AKO, pregnancy-associated mammary morphogenesis is severely impaired in the PR-BKO. By virtue of its ability to suppress E-induced and PR-B-mediated uterine and mammary proliferation, the PR-A isoform is likely to be an attractive drug target for the next generation of selective PR modulators in the treatment of uterine and mammary gland hyperplasia. Along with defining the dynamic interplay between E and P responses and physiological events mediated by PR-A and PR-B, further studies on these models should provide a broader conceptual framework for understanding abnormal progestin responses in vivo, with attendant implications for the management of female reproductive health and for the diagnosis and/or treatment of breast cancer.