Successful mammalian reproduction is dependent on a receptive and nurturing uterine environment. In order to establish pregnancy in humans, the uterus must i) be adequately prepared to receive the blastocyst, ii) engage in a coordinated molecular dialog with the embryo to facilitate implantation, and iii) undergo endometrial decidualization. Although numerous factors have been implicated in these essential processes, the precise network of molecular interactions that govern receptivity, embryo implantation, and decidualization remain unclear. NODAL, a morphogen in the transforming growth factor b superfamily, is well known for its critical functions during embryogenesis; however, recent studies have demonstrated an emerging role for NODAL signaling during early mammalian reproduction. Here, we review the established data and a recent wave of new studies implicating NODAL signaling components in uterine cycling, embryo implantation, and endometrial decidualization in humans and mice.Reproduction (2013) 145 R55-R64