In higher organisms, the response to stress plays an important role in optimizing the reactions and behavioral strategies in terms of perception, risk assessment and decision-making in the face of potential threats. However, the repeated solicitation of the biological systems underlying this response also imposes a negative burden on mental health by promoting mood-related disorders such as depression. The polyspecific organic cation transporters (OCTs) were shown previously to be sensitive to the hormone corticosterone in vitro in cultured cells, suggesting they might play a role in the physiological response to stress. In a recent study, we examined the implication of organic cation transporter 2 (OCT2) in the response to stress. We found that OCT2 is expressed in several stress-related circuits in the brain and along the hypothalamo-pituitary-adrenal (HPA) axis. Genetic deletion of OCT2 in mice strikingly enhanced the hormonal response to acute stress. As a consequence, OCT2-/- mice were potently more sensitive to the effects of chronic stress on depressive-like behaviors. The functional state of the GSK3β intracellular signaling pathway, highly responsive to acute and chronic stress, was altered in the hippocampus of OCT2-/- mice. In vivo pharmacology and Western blot experiments argue for increased serotonin tonus as a main mechanism for impaired Akt/GSK3 signaling in OCT2-/- mice brain. Our findings identify OCT2 as an important determinant of the response to stress in the brain, suggesting that in humans OCT2 mutations or blockade by diverse drugs may interfere with mood-related central functions and enhance vulnerability to repeated adverse events leading to depression.