During the past 10 years our knowledge about the pharmacotherapy of depression has been consolidated, and a variety of very interesting new compounds launched onto the market. The pipeline of the pharmaceutical industry is still filled with an assortment of new developments and very promising new approaches towards the pharmacotherapy of depressive disorders. Future pharmacological treatments of depression will not only enhance serotonergic and noradrenergic neurotransmission: other systems, such as the melatonergic receptor system and the hypothalamus-pituitary-adrenal axis, are also the targets of newly developed and upcoming substances with putative antidepressant effects. The main advantages of the currently available newer pharmacotherapeutic options are the broadening of the spectrum of possible antidepressant treatments, which is of particular importance for the growing number of patients suffering from difficult-to-treat depression, and a far better tolerability profile in comparison to older compounds such as tricyclic antidepressants. Unresolved issues are the unacceptably high rate of non-responsiveness during antidepressant treatment, a latency of sometimes several weeks until clinical improvement and remission can be achieved, and a variety of possible side effects also present during treatment with modern compounds. This review mainly presents the development of antidepressant pharmacotherapies during the past 10 years, together with pharmacokinetic and pharmacodynamic information and a comparison of different pharmacological treatment principles evaluated in randomized controlled clinical trials. In addition, new pharmacological strategies that are not yet available on the market and strategies currently under development are reviewed in detail. The study of new treatment options is of major importance to provide better strategies for the clinical management of depression in the future, and is thus also of great socio-economic importance.