The adult brain contains over 100 billion neurons, each of which connects to thousands of neuronal partners. Understanding how this large number of cells interacts to produce a complex organism behavior is an intellectual challenge of the highest order. Understanding synaptic function requires the determination of synaptic molecular components and their relative organization. For decades, the postsynaptic density of glutamatergic synapses was viewed as a compact mesh of randomly organized proteins. Fluorescence resonance energy transfer has proven to be extremely useful to measure activity dependent changes in interaction between synaptic proteins or between proteins and the membrane. Synaptic strength is the measure of the response of a given synapse to a given input and is determined by the complement of proteins expressed, also referred to as its “proteome”, and their post-translational modifications. Because of their complex morphology, neurons are faced with the challenge of maintaining and regulating up to thousands of synapses as individual units.