The role of serotonin (5-hydroxytryptamine; 5-HT) in the treatment of depressive and anxiety disorders is underscored by the therapeutic action of selective 5-HT reuptake inhibitors acting to enhance the degree of activation of various 5-HT receptor subtypes. The 5-HT1A receptors are particularly relevant to the antidepressant and anxiolytic responses in human beings. They are located presynaptically in the raphe nuclei, where they act as cell body autoreceptors to inhibit the firing rate of 5-HT neurons, and are located postsynaptically in limbic and cortical regions, where they also attenuate firing activity. The azapirones are full agonists at 5-HT1A autoreceptors and are generally, but not exclusively, partial agonists at postsynaptic 5-HT1A receptors. Some of these drugs, including gepirone and other 5-HT1A agonists such as buspirone, have been reported to exert anxiolytic and antidepressive activity in double-blind, placebo-controlled, and comparative trials. Their delayed therapeutic activity is believed to result from increased activation of postsynaptic 5-HT1A receptors occurring only after 5-HT neurons regain their normal firing activity. The recovery of this parameter, which is attributable to 5-HT1A autoreceptor desensitization, also restores 5-HT release. At this point, the summed effects of a normalized level of synaptic 5-HT and the exogenous 5-HT1A agonist can be exerted on postsynaptic 5-HT1A receptors. The widespread recognition of the clinical efficacy of such agents has largely been hampered by their undesirable pharmacokinetic properties. Most 5-HT1A agonists are indeed readily absorbed but are also rapidly eliminated, thereby often producing either suboptimal therapeutic responses at low doses, or cumbersome adverse effects at higher doses. Extended-release formulations allow once-daily dosing regimens, thus avoiding sharp peak plasma concentrations. This improves compliance and permits the use of higher dosages, which may be associated with enhanced efficacy and better tolerability relative to the immediate-release formulations. In sum, 5-HT1A receptor agonism represents a valuable and efficacious therapeutic approach to major depression.