Major depressive disorder is highly prevalent and remains inadequately treated. Numerous studies have demonstrated that modulation of ion channel activity can reduce depression-like behavior in animal models or depressive symptoms in humans. N-Methyl-D-aspartate and nicotinic acetylcholine receptor blockers have demonstrated promise as potential antidepressant agents in humans. Moreover, behavioral and physiological findings have provided evidence that the more recently characterized ion channel TWIK-related K+ channel-1 is a potential antidepressant target; however, drugs directed at this channel have yet to undergo clinical testing. Animal studies and genetic association findings also suggest that a number of other channel types, including voltage-gated calcium (N-type), potassium (Kv7), serotonin 5-HT3 and purinergic P2X7 channels, may influence depression-like behavior. The therapeutic utility of some ion channels will be limited by their role in multiple physiological or pathophysiological processes. Nevertheless, a number of strategies are being employed to provide improved specificity of action.