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Serotonin (5-HT)2Creceptors play an important role in the modulation of monoaminergic transmission, mood, motor behaviour, appetite and endocrine secretion, and alterations in their functional status have been detected in anxiodepressive states. Further, 5-HT2Csites are involved in the actions of several classes of anti-depressant. At the onset of treatment, indirect activation of 5-HT2Creceptors participates in the anxiogenic effects of selective 5-HT reuptake inhibitors (SSRIs) as well as their inhibition of sleep, sexual behaviour and appetite. Conversely, progressive down-regulation of 5-HT2Creceptors parallels the gradual onset of clinical efficacy of SSRIs. Other antidepressants, such as nefazodone or mirtazapine, act as direct antagonists of 5-HT2Creceptors. These observations underpin interest in 5-HT2Creceptor blockade as a strategy for treating depressive and anxious states. This notion is supported by findings that 5-HT2Creceptor antagonists stimulate dopaminergic and adrenergic pathways, exert antidepressant and anxiolytic actions in behavioural paradigms, and favour sleep and sexual function. In addition to selective antagonists, novel strategies for exploitation of 5-HT2Creceptors embrace inverse agonists, allosteric modulators, ligands of homo/heterodimers, modulators of interactions with ‘postsynaptic proteins’, dual melatonin agonists/5-HT2Creceptor antagonists and mixed 5-HT2C/α2-adrenergic antagonists. Intriguingly, there is evidence that stimulation of regionally discrete populations of 5-HT2Creceptors is effective in certain behavioural models of antidepressant activity, and promotes neurogenesis in the hippocampus. This article explains how these ostensibly paradoxical actions of 5-HT2Cantagonists and agonists can be reconciled and discusses both established and innovative strategies for the exploitation of 5-HT2Creceptors in the improved management of depressed and anxious states.