Pharmacology, clinical efficacy and tolerability of serotonin noradrenaline reuptake inhibitors(SNRIs) are overviewed. They include milnacipran, venlafaxine, duloxetine, MCI-225 and nefazodone, however, only milnacipran is currently used in Japan. Pharmacology of SNRIs is characterized by inhibition of both serotonin and noradrenaline at the presynaptic membrane and by weak affinity with receptors at the postsynaptic membrane, which expects the same efficacy on major depressive disorder(MDD) as tricyclic antidepressant drugs(TCAs) with less adverse effects in clinical use. Currently available evidences show that SNRIs possess antidepressant effects on MDD at least similar potencies to TCAs with more potencies than selective serotonin reuptake inhibitors. SNRIs are well tolerated in general and safer than TCAs. SNRIs can be considered to be first-line antidepressant drugs.