Classical tricyclic antidepressants (TA), still regarded as essential in the treatment of depression, are called by pharmacologists "dirty" due to the complex (not "clean") mechanism underlying action of these drugs, involving several types of neurotransmission. Numerous side effects are connected with such a complex action. At the same time it should be noted that basic TAs are characterized by a considerable effectiveness, so that Imipramine is still used as a reference point (a "golden standard") in the evaluation of new drugs efficacy. One of major directions in the development of contemporary psychopharmacology of depression is the striving to synthesize drugs showing a selective effect on neurotransmission, to be precise – affecting a single, specific system (NA or 5HT). Implementation of such drugs in the clinical practice involves a number of questions, concerning: mechanisms underlying their antidepressant action, pathogenesis of depression (i.e. which of the two neurotransmission systems is disordered: NA or 5HT), and effectiveness of medications selectively enhancing a specific type of neurotransmission. These problems have not been elucidated so far, and research findings reported in the literature are inconsistent. Undoubtedly, antidepressants with selective action are safer than TAs – however, it is not clear yet whether they are equally effective. It can be hoped that these controversial problems may be settled due to the implementation in clinical practice of antidepressants affecting both the NA and 5HT systems, but having no influence on other types of neurotransmission (DA, ACh, Hl and H2 receptors). The latter group of drugs, interesting to theorists and promising to clinicians, require further controlled clinical trials and verification in a wide-range clinical practice. Above all, their therapeutic action should be compared with that of drugs selectively affecting neurotransmission.