Signaling between neurons depends on a highly ordered and regulated distribution of proteins at the synapse. Neurotransmitter receptors are clustered in the postsynaptic cell in precise juxtaposition to the sites of neurotransmitter release in the presynaptic cell, ensuring rapid and efficient synaptic transmission. The bulk of our knowledge about the molecular mechanisms underlying synaptogenesis comes from studies of the neuromuscular junction (NMJ), the synapse between a motor neuron and a muscle fiber. In the end plate region of the muscle cell, nicotinic acetylcholine receptors (AChR) are amassed to a density that approaches 10,000 per m2. The density drops by 1000-fold just microns outside the synapse. 1, 2 Disruption of this specialized postsynaptic machinery, as occurs in acquired myasthenia gravis, has serious consequences for synaptic transmission and muscle contraction. Although the signal transduction pathways underlying the initiation and maintenance of the postsynaptic specialization have not been well characterized, many lines of evidence suggest that tyrosine phosphorylation may be centrally important (see below). This chapter reviews recent experiments from our laboratory demonstrating that tyrosine phosphorylation of the AChR itself may be involved in the initiation of a signal transduction pathway through its interaction with the modular adaptor protein Grb2. 3