While the indispensability of the progesterone receptor (PR) in female reproduction and mammary morphogenesis is acknowledged, the coregulators preferentially recruited by PR to mediate its in vivo effects have yet to be fully delineated. To further parse the roles of steroid receptor coactivator (SRC)/p160 family members in P-dependent physiological processes, genetic approaches were employed to generate a mouse model (PR^Cre/+SRC-2^flox/flox) in which SRC-2 function was ablated specifically in cell-types that express the PR. Fertility evaluation revealed that while ovulation occurred normally in the PR^Cre/+SRC-2^flox/flox mouse, uterine function was markedly affected. Absence of SRC-2 in PR positive uterine cells contributed to an early block in embryo implantation, a phenotype not shared by knockouts for SRC-1 or -3. Although the PR^Cre/+SRC-2^flox/flox uterus could mount a partial decidual response, removal of SRC-1 in the PR^Cre/+SRC-2^flox/flox uterus resulted in a complete block in decidualization, confirming that uterine SRC-2 and -1 are both required for P-initiated transcriptional programs which lead to full decidualization. In the case of the mammary gland, whole-mount and histological analyses revealed the absence of significant branching morphogenesis in the hormone-treated PR^Cre/+SRC-2^flox/flox mammary gland, reinforcing an important role for mammary SRC-2 in cellular proliferative events that require PR. Based on the above and the observation that SRC-2 is expressed in many of the uterine and mammary cell-lineages in the human as observed in the mouse, we suggest that further investigations are warranted to gain additional insights into SRC-2's involvement in normal (and possibly abnormal) uterine and mammary cellular responses to progestins.