A characteristic feature of antidepressant therapy is the lag phase in onset of clinical efficacy. This applies to both typical tricyclics agents and atypical antidepressants, mianserin or maprotiline. Attempts to delineate the molecular mechanisms of action of antidepressants on the basis of acute studies are limited value, and increasing attention is being focused on resultant adaptive changes stemming from their chronic treatment. The drug-induced adaptive modification can occur both pre-and postsynaptically. Regarding presynaptic sites, adaptation in the synthesis and release of norepinephrine (NE) and presynaptic alpha2-receptors and dopamine autoreceptors occur. However, the changes cannot be regarded as being primarily responsible for the therapeutic action of antidepressants. Chronic antidepressant treatments affect also post-synaptic aminergic systems eliciting a reduction of beta-adrenoceptors and in the sensitivity of NE-stimulated adenylate cyclase (NE-AC), and a decrease of 5HT2-receptors. The postsynaptic changes are more pertinent to the mechanisms of action of the drug. However, these properties can not extend to all atypical antidepressants. Fluoxetine, trazodone, alprazolam or MIA fails to alter beta-receptor density or the NE-AC sensitivity, and electroconvulsive therapy produces an increases in 5HT2 sites. More recently, new experiments demonstrate 1) a biomolecular linkage between 5HT and NE neuronal systems at the level of beta-receptors; 2) an acceleration of beta-receptor reduction with combined administration of antidepressants and alpha 2-receptor antagonists; 3) an existence of imipramine-like substance (endocoid) in the brain and a reduction of [3H]imipramine binding sites after chronic treatment with imipramine. While the end result downstream may be the same clinical efficacy, the initial biochemical steps leading to this goal may not be identical for all forms of antidepressants. It is expected that the new approaches can lead to the finding a common mechanism of action to all form of antidepressants.