In spite of recent progress in the pharmacotherapy of depression, major issues are still unresolved. These include the nonresponse rate of approximately 30% to conventional antidepressant pharmacotherapy, side effects of available antidepressants, and the latency period of several weeks until clinical improvement. Current treatment strategies aim to enhance serotonergic and/or noradrenergic neurotransmission. However, in the meantime, several new pharmacological principles are under investigation with regard to their antidepressant potency. Placebo-controlled, double-blind studies have been performed with 5-HT(1A) receptor agonists and tachykinin receptor antagonists which point towards antidepressant efficacy. While there is some evidence for putative antidepressant properties of various interventions within the hypothalamic-pituitary-adrenal system such as CRH(1) receptor antagonists, steroid synthesis inhibitors, and glucocorticoid receptor antagonists in animal studies, case series, open studies, and small placebo-controlled studies, no definite proof for their antidepressant efficacy has been furnished. Nevertheless, follow-up of new pharmacological strategies is of major importance to provide even better strategies for the clinical management of depression, which also has great socioeconomic impact.