Epithelial-mesenchymal interactions play a crucial role in the correct patterning of the mammalian female reproductive tract (FRT). Three members of the Wnt family of growth factors are expressed at high levels in the developing FRT in the mouse embryo. The expression of Wnt genes is maintained in the adult FRT, although levels fluctuate during estrous. Wnt4 is required for Müllerian duct initiation, whereas Wnt7a is required for subsequent differentiation. In this study, we show that Wnt5a is required for posterior growth of the FRT. We further demonstrate that the mutant FRT has the potential to form the posterior compartments of the FRT using grafting techniques. Postnatally, Wnt5a plays a crucial role in the generation of uterine glands and is required for cellular and molecular responses to exogenous estrogens. Finally, we show that Wnt5a participates in a regulatory loop with other FRT patterning genes including Wnt7a, Hoxa10 and Hoxa11. Data presented provide a mechanistic basis for how uterine stroma mediates both developmental and estrogen-mediated changes in the epithelium and demonstrates that Wnt5a is a key component in this process. The similarities of the Wnt5a and Wnt7a mutant FRT phenotypes to those described for the Hoxa11 and Hoxa13 mutant FRT phenotypes reveal a mechanism whereby Wnt and Hox genes cooperate to pattern the FRT along the anteroposterior axis.