The neuromuscular junction is characterized by precise alignment between the nerve terminal and the postsynaptic apparatus formed by the muscle fiber. Organization of the neuromuscular junction during embryonic development, growth, and maintenance is coordinated by signals exchanged between motor neurons and their target muscle fibers. Identification of proteins such as agrin, likely to represent neuronal agents that direct the organization of the postsynaptic apparatus, has focused attention on characterization of proteins that mediate retrograde signals that regulate the organization and function of the nerve terminal. The results of these studies implicate a role for both adhesive and diffusible signals in coordinating the development, maturation, and maintenance of the motor nerve terminal. The diversity of molecules identified to date that appear to play a role in these processes implies a considerable level of redundancy in the transduction pathway. However, studies of early nerve-muscle interactions suggest that a common feature of many of these retrograde agents is activation of a protein kinase coupled with an increase in cytosolic Ca2+ concentration. While the molecular signals that regulate growth and maintenance of neuromuscular junctions are less well understood it seems likely that similar adhesive and diffusible factors will be involved.