As neuromuscular junctions form in vertebrate skeletal muscle, nicotinic acetylcholine receptors (AChRs) become concentrated in the postsynaptic membrane. The nerve directs this redistribution, using multiple signals to regulate AChRs at both transcriptional and post-translational levels. Recent studies in vitro have led to the identification of candidate nerve-derived signaling molecules (such as agrin, ARIA/neuregulin, and calcitonin gene-related peptide) and components of their intramuscular signaling pathways (including dystroglycan, MuSK, erbB kinases, utrophin, and rapsyn). Studies of knock-out mice are now making it possible to test which signals and pathways are responsible for postsynaptic differentiation in vivo.