5-hydroxytryptamine (5-HT; serotonin) is a neurotransmitter essential for a large number of physiological processes including the regulation of vascular and non-vascular smooth muscle contraction, modulation of platelet aggregation, and the regulation of appetite, mood, anxiety, wakefulness and perception. To mediate this astonishing array of functions, no fewer than 15 separate receptors have evolved, of which all but two (5-HT(3A) and 5-HT(3B)) are G-protein coupled receptors. This review will summarize our current understanding of the structure and function of the G-protein coupled 5-HT receptors. In particular, a systematic review of the available mutagenesis studies of 5-HT receptors will be presented. This information will be synthesized to provide a working model of agonist and antagonist actions at a prototypic 5-HT receptor the 5-HT(2A) receptor. Finally, examples will be given to demonstrate that a detailed knowledge of the predicted structure of one receptor can be useful for structure-based drug design.