Depression is the most common illness that affects a large number of individuals in all countries. Recent evidence suggest that depressive episodes if left untreated may heighten severity of subsequent episodes and may increase need for more health care resources. The first antidepressants, tricyclics and monoamine oxidase inhibitors, became available in the late 1950s. A progressive tightening of requirements by drug licensing authorities has ensured that efficacy evidence is good for most antidepressants that are in use. Contemporary antidepressant classification system is based on the mechanism of action, which is presumed to be responsible for their antidepressant effects. A pharmacodynamic system of classification has advantages because it incorporates the current theories of disease pathophysiology. Understanding the basic aspects of mechanism of action of antidepressants is important for treatment of depressive episode, for development of augmenting strategies and combining antidepressants with other antidepressants or antipsychotics. Antidepressants as a class of psychotropic medication have the broad range of indications. The choice of initial antidepressant legitimately varies considerably among clinicians and countries. Referring to some differences of recommendations for the first line treatment of depressive episode we suppose that the choice of antidepressant medication must be individualized for a particular patient. Novel antidepressants (SSRI, SNRI, NaSSA, NARI, NDRI and other) are safe and better tolerated. Metabolism of novel antidepressants is much improved compared with MAOIs and TCAs. The combination of antidepressants is an important clinical issue. There are the following principles of combining antidepressants: 1. to combine mechanisms of action not just drugs, 2. to combine antidepressants and to promote pharmacological synergy and tolerability, 3. to use important synergies within the serotonin, noradrenaline and even dopamine monoaminergic systems. Adequate treatment of depression including modern treatment approaches has the potential to reduce suffering and disability substantially and minimise the risk of suicide.