Preclinical and clinical studies support the rationale that development of single molecules, which would promote serotonergic and noradrenergic neurotransmission by inhibiting simultaneously the uptake of both monoamines, would potentially result in improved antidepressant drugs. Currently, the dual inhibitors of serotonin and noradrenaline uptake are venlafaxine, milnacipran and duloxetine. Based on the preclinical studies, the three drugs do show properties of inhibiting uptake of both monoamines in vitro and in vivo in the following order of decreasing potency: duloxetine, venlafaxine and milnacipran, and all exhibit low affinity at neuronal receptors of neurotransmitters, suggesting low side-effect potential. In double-blind, controlled studies, venlafaxine and milnacipran were repeatedly shown to be as efficacious as tricyclic antidepressant drugs in treating major depressive disorder, while one double-blind, placebo-controlled trial showed the antidepressant efficacy of duloxetine. Specifically designed comparative trials of dual uptake inhibitors against the other agents are needed to establish whether the dual uptake inhibitors show improvement in efficacy, rate of responders, antidepressive effects and/or remission.