RECEPTOR tyrosine kinases (RTKs) are cell-surface molecules that transduce signals for cell growth and differentiation1. The RTK encoded by the c-ret proto-oncogene2-5 is rearranged and constitutively activated in a large proportion of thyroid papillary carcinomas6, and germ-line point mutations in c-ret seem to be responsible for the dominantly inherited cancer syndromes multiple endocrine neoplasia (MEN) types 2A7,8 and B-9. The gene is expressed in the developing central and peripheral nervous systems (sensory, autonomic and enteric ganglia) and the excretory system (Wolffian duct and ureteric bud epithelium) of mice, indicating that it may play a role in normal development5. Here we show that mice homozygous for a targeted mutation in c-ret develop to term, but die soon after birth, showing renal agenesis or severe dysgenesis, and lacking enteric neurons throughout the digestive tract. Ret is thus an essential component of a signalling pathway required for renal organogenesis and enteric neurogenesis.