In the 1950s, the first antidepressant drugs, the tricyclic antidepressant (TCA) imipramine and the monoamine oxidase inhibitor (MAOI) iproniazid, were introduced. However, these drugs had 3 particular drawbacks. Firstly, a lag time of several weeks before clinically therapeutic effects was observed. Secondly, the agents were only effective in relieving symptoms in approximately two-thirds of patients. Thirdly, due to their non-selective nature, they were associated with a variety of unpleasant and in some cases fatal adverse effects. The more recently introduced drugs have an improved safety profile, but not a quicker onset or more effective. New targets have emerged as a consequence of our increasing knowledge of the neurochemical, endocrine and immunological changes associated with depression. Study of the hypothalamic-pituitary-adrenal (HPA) axis has resulted in the development of corticotrophin releasing hormone (CRH) antagonists, glucocorticoid synthesis inhibitors and glucocorticoid receptor antagonists. Neuropeptide targets have included neuropeptide Y (NPY) and neurokinin (NK) receptors. Alterations in immune function in depression have led to the proposal that cytokines may hold the key. Reinvestigating the process of monoamine neurotransmission has largely centred on the serotonergic system, as well as the NMDA receptor, and intracellular signalling mechanisms. The most developed of these approaches at present are those associated with the serotonergic, HPA axis and neuropeptide targets. The plethora of targets and the sustained development of chemical entities with greater selectivity and bioavailability provide the hope that these approaches will result in the development of antidepressants with truly novel mechanisms of action.