During the past years substanial knowledge has been obtained both in diagnostics and pharmacotherapy of unipolar depression. Today it is well-established that perturbation of the monoaminergic neurotransmission pathway is implicated in the development of depressive states, and that all currently existing antidepressants act on depressive symptoms by controlling monoamine availability at the synaptic level. According to the data obtained in Europe, it is apparent that these treatments are efficient in only 60–70% of depressed patients and their onset of action is partly delayed by 4–5 weeks. With novel pharmacological approaches recently being introduced, these figures can be improved. With the introduction of agomelatine, for instance, which affects the melatonergic as well as serotonergic pathways, higher response rates than with conventional antidepressants have been demonstrated. Furthermore, treatment of therapy resistance has been advanced with the introduction of atypical antipsychotics. For treatment refractory patients, brain stimulation as well as vagus nerve stimulation showed promising results although the later two methods are only possible in specific treatment centers. The advances in pharmacogenomics and sequencing of the human genome promise for the future to have molecular targets which have not as yet reached the daily practice. The search for new antidepressants based on these considerations has not been completed and the recent findings are promising for the future in regards to research and treatment. The lecture will include data on the neuropsychopharmacological understanding furthermore the future perspectives of treatment approaches will be discussed.