Although depression is a common disorder that is often resistant to pharmacotherapy, its pathophysiology has remained elusive. Since the early 1950s, when the first antidepressants were introduced, i.e., the non-selective MAO inhibitors and tricyclic drugs, a number of hypotheses describing ethiopathogenesis of depression and antidepressant drug action have been formulated. The Institute of Pharmacology, the Polish Academy of Sciences has performed experimental and clinical research focused on the pathophysiology of depression and the mechanisms of action of antidepressant drugs for over 40 years. Our results from this period have significantly contributed to understanding the complex mechanisms of antidepressant drug actions and new pathways that underpin the pathophysiology of depression. Most of these theories are based on the finding that the chronic administration of antidepressants leads to adaptive changes in pre- and post-synaptic monoaminergic and glutamatergic neurotransmission as well as to alterations in gene transcription and immune-inflammatory and neurotrophic factors, resulting in neuroplastic changes in the brain. Taking into account the functional interdependence of the neuronal, hormonal and immunologic systems, we propose neurodevelopmental and neuroimmune theories for affective disorders. Moreover, commonalities have been documented for the pathomechanisms of depression and neurodegenerative and metabolic disorders as well as drug dependence. The aim of this special issue is to briefly present the major research contributions and the new research directions of the Institute of Pharmacology, the Polish Academy of Sciences with respect to the neurobiology of affective disorders and the mechanisms of action of marketed and new putative antidepressant drugs.