The clustering of acetylcholine receptors (AChRs) in muscle is a hallmark step in the development of vertebrate neuromuscular junctions (NMJs). It involves localized signaling, which is initiated by the activation of MuSK (muscle-specific kinase) and leads to the concentration and cytoskeletal anchoring of AChRs at the synapse, and global signaling, which traverses the muscle to disperse extra-synaptic AChR clusters. Here we review some of the recent findings that indicate important roles for the actin cytoskeleton and tyrosine phosphatases in mediating these processes.