Major depressive disorder (MDD) is a highly prevalent and disabling condition for which the currently available treatments are not fully effective. Existing unmet needs include rapid onset of action and optimal management of concurrent agitation. Dexmedetomidine (DEX) is a selective and potent α2-adrenergic receptor (α2-AR) agonist, with unique pharmacokinetic and pharmacodynamic properties. In this review, we discuss pre-clinical and clinical studies which focused on DEX in the context of its putative antidepressant effects for the management of MDD. Preliminary data support DEX as an antidepressant with fast onset of action, which would be especially helpful for patients experiencing treatment resistant depression, and agitation. We further explore the mechanistic and clinical implications of considering DEX as a putative antidepressant agent, and the next steps to explore the efficacy of low dose DEX infusion among patients with treatment resistant depression.