The sympathetic, parasympathetic and enteric ganglia are the main components of the peripheral autonomic nervous system(1), and are all derived from the neural crest(2). The factors needed for these structures to develop include the transcription factor Mash 1 (refs 3-5), the glial-derived neurotrophic factor GNDF (refs 6-8) and its receptor subunits(9-12), and the neuregulin signalling system(13), each of which is essential for the differentiation and survival of subsets of autonomic neurons. Here we show that all autonomic ganglia fail to form properly and degenerate in mice lacking the homeodomain transcription factor Phox2b, as do the three cranial sensory ganglia that are part of the autonomic reflex circuits. in the anlagen of the enteric nervous system and the sympathetic ganglia, Phox2b is needed for the expression of the GDNF-receptor subunit Ret and for maintaining Mash1 expression. Mutant ganglionic anlagen also fail to switch on the genes that encode two enzymes needed for the biosynthesis of the neurotransmitter noradrenaline, dopamine-beta-hydroxylase and tyrosine hydroxylase, demonstrating that Phox2b regulates the noradrenergic phenotype in vertebrates.