The RET tyrosine kinase is required for the migration, proliferation, and survival of the enteric neural crest-derived cells (ENCCs) that form the enteric nervous system (ENS). Hypomorphic RET alleles cause intestinal aganglionosis [Hirschsprung disease (HSCR)], in which delayed migration and successive nonapoptotic ENCC death are considered to be major contributory factors. The significance of ENCC death in intestinal aganglionosis, however, has remained unclear. We show that elevated expression of Bcl-xL inhibits ENCC death in both Ret-null and hypomorphic states. However, the rescued Ret-null mice showed ENS malfunction with reduced nitric oxide synthase expression in colonic neurons, revealing the requirement of RET for neuronal differentiation. In contrast, the inhibition of cell death allows morphologically and functionally normal ENS formation in Ret hypomorphic mice. These results indicate that ENCC death is a principal cause of intestinal aganglionosis in a Ret hypomorphic state, and suggest that the inhibition of cell death is a route to the prevention of HSCR.