Although antidepressant treatments produce clear effects on monoaminergic neuronal function, the link between these effects and therapeutic response to treatment is controversial. Previous studies have demonstrated that antagonists of the NMDA receptor-gated calcium ionophore result in antidepressant-like responses in rodents and humans. Likewise, antidepressant treatments produce regionally selective adaptation of the NMDA receptor suggestive of diminished capacity to gate calcium into receptive neurons. Similarly, voltage-dependent calcium channel antagonists have been reported to produce antidepressant-like effects in rodents. A major target of increases in subcellular calcium concentration is nitric oxide synthase (NOS) which liberates NO in response to stimulation. Recently, we have demonstrated that nitric oxide synthase antagonists produced antidepressant-like response in both in vivo preclinical screening procedures and in post-mortem in vitro studies of β-adrenoceptor density. We propose: 1) that interruption of the Ca2+-calmodulin-NOS-guanylyl cyclase subcellular signaling pathway at any point will produce antidepressant-like effects; 2) that the acute actions of antidepressants in preclinical screening procedures are a consequence of their ability to disrupt Ca2+-calmodulin-NOS-guanylyl cyclase signaling; 3) that chronic but, not acute treatment with antidepressants results in adaptation of the Ca2+-calmodulin-NOS-guanylyl cyclase signaling pathway; 4) that this adaptation is necessary for the achievement of the therapeutic actions of antidepressants and; 5) that major depression is accompanied by an alteration (hyperactivity?) of subcellular Ca2+ signaling. Copyright © 2001 John Wiley & Sons, Ltd.