Nodal-related ligands of the transforming growth factor-beta (TGFbeta) superfamily play central roles in patterning the early embryo during the induction of mesoderm and endoderm and the specification of left-right asymmetry. Additional roles for this pathway in the maintenance of embryonic stem cell pluripotency and in carcinogenesis have been uncovered more recently. Consistent with its crucial developmental functions, Nodal signaling is tightly regulated by diverse mechanisms including the control of ligand processing, utilization of co-receptors, expression of soluble antagonists, as well as positive- and negative-feedback activities.