Synaptic transmission underlies every aspect of brain function. Excitatory synapses, which release the neurotransmitter glutamate, are the most numerous type of synapse in the brain. The trafficking of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type glutamate receptors to and from these synapses controls the strength of excitatory synaptic transmission. However, the underlying mechanisms controlling this trafficking have remained elusive. Recent studies, drawing from advances in molecular biology and electrophysiology techniques, have established an essential role for a family of synaptic scaffolding molecules, known as membrane associate guanylate kinases (MAGUKs), in this trafficking process. These studies highlight the remarkable orchestration of AMPA-type glutamate receptor synaptic trafficking by multiple MAGUKs at different synapses within the same neuron and at different developmental stages.