Rapid signal transduction at chemical synapses involves calcium-dependent neurotransmitter release from presynaptic neurons, binding of transmitter to ligand-gated ion channels located primarily on the postsynaptic membrane, and subsequent uptake of transmitter by way of sodium-coupled neurotransmitter transporters. Chemical synapses can be defined by the released neurotransmitter and the class of receptor activated by the transmitter. The major classes of neurotransmitter receptors are, on the one hand, cation-permeable excitatory receptors and, on the other hand, anion-permeable inhibitory receptors. Whereas tetrameric ionotropic glutamate receptors that include AMPA, kainate and NMDA receptors are the primary neurotransmitter receptors that mediate fast excitatory neurotransmission, the pentameric, Cys-loop GABA and glycine receptors encompass the major group of receptors that participate in fast inhibitory neurotransmission. There are additional Cys-loop receptors, however, that are selective for cations, and these include the excitatory acetylcholine and serotonin receptors. Trimeric ATP-gated P2X receptors, together with the similarly trimeric yet amino acid sequence disparate acid-sensing ion channels define a final class of cation permeable receptors present in the central nervous system. To resolve fundamental questions of receptor architecture and molecular mechanism, my research group has embarked on studies of neurotransmitter receptors using x-ray crystallographic, electrophysiological and biochemical methods. We are particularly interested in understanding the mechanism by which agonist binding leads to receptor activation, the molecular principles that underlie receptor desensitization or inactivation, and the chemical and structural basis for ion selectivity, ion channel block and allosteric modulation of receptor activity. Over the past several years we have elaborated the atomic structures of intact trimeric acid sensing ion channels and ATP-gated P2X receptors, tetrameric AMPA receptors and pentameric Cys-loop receptors in multiple conformational states and in complexes with a wide array of agonists, antagonists, toxins, ions and allosteric modulators. Here I will define the overall architectures of these receptors and provide molecular mechanisms for their activities at chemical synapses that are grounded in experimental structural data at atomic resolution.