Nodal ligands are essential for the patterning of chordate embryos. Genetic evidence indicates that EGF-CFC factors are required for Nodal signaling, but the molecular basis for this requirement is unknown. We have investigated the role of Cripto, an EGF-CFC factor, in Nodal signaling. We find that Cripto interacts with the type I receptor ALK4 via the conserved CFC motif in Cripto. Cripto interaction with ALK4 is necessary both for Nodal binding to the ALK4/ActR-IIB receptor complex and for Smad2 activation by Nodal. We also find that Nodal can inhibit BMP signaling by a Cripto-independent mechanism. Inhibition appears to be mediated by heterodimerization between Nodal and BMPs, indicating that antagonism between Nodal and BMPs can occur at the level of dimeric ligand production.