The uterus is an essential organ for reproduction in mammals. Despite the importance of the uterus for the fertility and health of women and their offspring, relatively little is known about the hormonal, cellular, and molecular mechanisms that regulate development of the uterus in either the fetus or neonate. Disruption of uterine development in the fetus and neonate by genetic defects or exposure to endocrine disruptors can program the function of the uterus in the adult and lead to infertility, cancer, and even death. The intent of this chapter is to review the current knowledge of regulatory factors and pathways governing prenatal organogenesis and postnatal morphogenesis of the uterus in mammals, with a particular focus on laboratory and domestic animals. Prenatal organogenesis, postnatal morphogenesis, and adult functional differentiation of the uterus are complex, multifactorial processes. Although conservation of some factors and pathways are observed between species, it is clear that mutation of candidate genes in the mouse does not always recapitulate the same defects observed in the human. Therefore, comparative biology of the mechanisms regulating uterine development in other species may be useful to identify candidate genes and pathways to understand congenital abnormalities in humans. This knowledge is necessary to develop rational therapies to prevent and treat infertility and to enhance fertility in humans and domestic animals.