An enhancement of neurotransmission of serotonin (5-HT), noradrenaline, or both, underlies the antidepressant response associated with most agents presently available to treat major depression. With respect to the 5-HT system, antidepressant drugs exert immediate effects on some neuronal elements controlling overall transmission, but it is the gradual changes in neuronal responses to such treatments that are ultimately responsible for producing their therapeutic benefits. In major depression, an increase in 5-HT1A transmission is thought to be a crucial determinant of the antidepressant response, whereas an enhancement of 5-HT2 transmission in the orbitofrontal cortex may mediate the therapeutic effect of 5-HT reuptake inhibitors in obsessive-compulsive disorder (OCD). The doses of medication and the durations of treatment necessary to obtain these alterations in 5-HT transmission in various brain structures of laboratory animals are fully consistent with the conditions in the clinic necessary to attenuate symptoms in depression and OCD. It is also possible that the relief of chronic pain produced by some antidepressants may be mediated, in part, by the blockade of peripheral 5-HT2A receptors. These observations emphasize the notion that the 5-HT system is endowed with different adaptive properties in various parts of the body, which, in addition to the multiplicity of 5-HT receptors, makes this chemospecific network important in many disorders.