Considering the ever growing number of new discoveries and changes in ideas in the field of psychopharmacology, the authors present the actual state of knowledge about the mechanism of action of antidepressant drugs. Three periods characterize the research and the development of antidepressants. In the first period the presynaptic monoamine neuron was considered as the target structure both with respect to the search for the origin of depression and the mechanism of action of antidepressants. Two types of antidepressants, monoamine uptake inhibitors and monoamine oxidase inhibitors (IMAO) are representative of this period. In the second period, the research focused its interest primarily on monoaminergic receptors, anticipating that they were critically involved in the pathophysiology of depression. Such research sought to explain the antidepressant properties of iprindole and mianserine which are neither monoamine uptake inhibitors nor inhibitors of MAO. The onset of the third period is recent and it is characterized by the shift in research emphasis to intracellular transmission events. This period started with the discovery of the antidepressant properties of the phosphodiesterase inhibitor rolipram.