Depression is a brain disorder characterized by severe emotional, cognitive, neuroendocrine and somatic dysfunction. Although the latest generation of antidepressant drugs has improved clinical efficacy and safety, the onset of their clinical effect is significantly delayed after treatment commencement, and a large number of patients exhibit inadequate response to these drugs and/or depression relapse even following initially successful treatment. It is therefore essential to develop new antidepressant drugs and/or adjuncts to existing ones. Recent studies suggest that the beneficial effect of antidepressant drugs is mediated, at least in part, via stimulation of adult hippocampal neurogenesis and subsequent increase in hippocampal plasticity. Since the stimulatory effect of antidepressant drugs on hippocampal neurogenesis involves G-protein coupled receptors (GPCR) and voltage-dependent calcium channels (VDCC), greater efficacy may be available if future antidepressant drugs directly target these specific GPCR and VDCC. The potential advantages and limitations of these treatment strategies are discussed in the article.