TGF-β subfamily ligands signal via a receptor complex composed of two type II receptors and two type I receptors [14,15]. Ligand binding leads to phosphorylation and activation of type I receptors, which, in turn, phosphorylate and activate a specific set of downstream signaling molecules called Smads. In general terms, TGF-βs bind to the TGF-β type II receptor (TGFβRII) and TGF-β type I receptor (ALK5) activating TGF-β Smads (2 and 3), while BMPs bind to the BMP type II receptor and type I receptors ALK2, -3, or 6, activating BMP Smads (1, 5 and 8). However, it is likely that these signaling interactions are more complex in vivo, possibly allowing formation of heterotetrameric complexes composed of different type II and type I receptors [16]. In addition, recent studies have identified novel TGF-β-related ligands, which can bind to entire different combinations of receptors. For instance, growth and differentiation factors (GDFs) 8 and 9 can bind to Activin type II receptor and ALK5 to activate TGF-β Smads [17,18]. Therefore, we hypothesized that deletion of Alk5 in a specific cell lineage should reveal phenotypes which cannot be seen in comparable mutants lacking Tgfbr2. Indeed, we recently showed that neural crest cell specific Alk5 mutants display a unique spectrum of craniofacial developmental defects, e.g., cleft snout and severe mandibular hypoplasia [19]; these phenotypes were not seen in corresponding Tgfbr2 mutants [20]. To determine, whether ALK5 would also mediate unique non-redundant signaling events in cardiac neural crest cells, we focused on cardiac and pharyngeal phenotypes of mouse embryos lacking Alk5 specifically in neural crest cells. We discovered that in Alk5/Wnt1-Cre mutants, pharyngeal organs (thymus and parathyroid) fail to migrate appropriately. Moreover, the mutant embryos display severe aortic sac and pharyngeal arch artery defects, and failed aortico-pulmonary septation leading to PTA. Our data further suggest that at least some of these abnormal detected phenotypes result from a dramatic increase in apoptosis of postmigratory cardiac neural crest cells. These phenotypes differ remarkably from those seen in corresponding Tgfbr2 mutants, suggesting that ALK5 mediates a wider spectrum of signaling events than its classical binding partner TGFβRII in cardiac neural crest cells during cardiac and pharyngeal development.