MUTATIONAL analysis in humans and mice has demonstrated that Ret, the product of the c-ret proto-oncogene, a member of the receptor tyrosine kinase (RTK) superfamily(1), is essential for development of the enteric nervous system and kidney(2-6). Despite the established role of Ret in mammalian embryogenesis, its cognate ligand(s) is currently unknown. Here we demonstrate, by using a Xenopus embryo bioassay, that glial-cell-line-derived neurotrophic factor (GDNF)(7), a distant member of the transforming growth factor(TGF)-beta superfamily, signals through the Ret RTK. Furthermore, using explant cultures from wild-type and Ret-deficient mouse embryos(4), we show that normal c-ret function is necessary for GDNF signalling in the peripheral nervous system, Our data strongly suggest that Ret is a functional receptor for GDNF, and that GDNF, in addition to its potential role in the differentiation and survival of central nervous system neurons(8-12), has profound effects on kidney organogenesis and the development of the peripheral nervous system.