In spite of recent progress in the pharmacotherapy of depression major issues are still unresolved. These include the non-response rate of approximately 30% to conventional antidepressant pharmacotherapy, side effects of available antidepressants and the latency of several weeks until clinical improvement. The only non-pharmacological biological treatment options available so far which exert more rapid antidepressant efficacy are electroconvulsive therapy and, as an augmentation strategy, sleep deprivation. Current pharmacological treatments aim to enhance serotonergic and/or noradrenergic neurotransmission. In spite of emerging knowledge, the crucial mechanisms underlying both non-pharmacological treatments, which are responsible for antidepressant efficacy, are not yet clear so far. In the meantime several new pharmacological principles are under investigation with regard to their putative antidepressant potency. These include 5-HT1A receptor agonists, tachykinin receptor antagonists and various interventions within the hypothalamic-pituitary-adrenal system. While there is evidence for antidepressant properties of these new treatments in animal studies, in case series, in open studies and to some degree also in placebo controlled studies, no definite proof for the antidepressant efficacy of these new pharmacological strategies according to the requirements for evaluation of antidepressant drugs has been furnished so far. In contrast, for the established non-pharmacological treatment strategies including bright light therapy the clinical efficacy has been proven at least in subgroups of depression, but more knowledge of the main mechanisms underlying their antidepressant efficacy is still necessary. In addition new non-pharmacological treatments like repetitive transcranial magnetic stimulation, magnetic seizure therapy and Vagus nerve stimulation are currently under development. Nevertheless, a follow-up of both the new pharmacological strategies and non-pharmacological treatment options is of major importance to provide even better strategies for the clinical management of depression, which also is of great socio-economic impact.