Dissecting the mechanisms of synaptic transmission touches on nearly all fields of neuroscience. Of particular recent importance is the discovery that protein distribution within single synapses is highly organized across multiple spatial scales, ranging from the nanoscale accumulation of just a few protein molecules to larger domains with unique multiprotein compositions. Here, we address recent data regarding postsynaptic molecular organization. We argue that the complexity of synaptic nanostructure generates functional capabilities that can fine-tune synaptic strength and that far exceed the classical limits of quantal synaptic transmission. We focus first on the critical scaffold protein PSD-95 as a case study for how to approach the emergent problem of describing and classifying forms of protein organization, including trans-synaptic “nanocolumn” relationships. Then, we discuss recent work identifying new features of NMDA receptor subsynaptic organization that appear likely to regulate the patterns of neural activity that can induce synaptic plasticity. Overall, we assert that these mechanisms of molecular coordination at scales of 20–150 nm enhance the synapse’sSynapse ability to tune synaptic transmission, carry out detailed biochemical signaling, and allow more complex impacts on the cell.