Normal brain function requires the faithful transmission and integration of information on a timescale of milliseconds, and this rapid signaling is mediated by cell membrane receptors that are ligand-gated ion channels. Fast excitatory transmission occurs when synaptically released glutamate opens channels in neighboring neurons, but these channels desensitize rapidly during sustained high-frequency firing. Recent structural data have begun to provide important insights into the molecular mechanisms that underlie channel activation and desensitization.