Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed medications for psychiatric disorders, yet they leave the majority of patients without full symptom relief. Therefore, a major research challenge is to identify novel targets for the improved treatment of these disorders. SSRIs act by blocking the serotonin transporter (SERT), the high-affinity, low-capacity, uptake-1 transporter for serotonin. Other classes of antidepressant work by blocking the norepinephrine or dopamine transporters (NET and DAT), the high-affinity, low-capacity uptake-1 transporters for norepinephrine and dopamine, or by blocking combinations of SERT, NET, and DAT. It has been proposed that uptake-2 transporters, which include organic cation transporters (OCTs) and the plasma membrane monoamine transporter (PMAT), undermine the therapeutic utility of uptake-1 acting antidepressants. Uptake-2 transporters for monoamines have low affinity for these neurotransmitters, but a high capacity to transport them. Thus, activity of these transporters may limit the increase of extracellular monoamines thought to be essential for ultimate therapeutic benefit. Here preclinical evidence supporting a role for OCT2, OCT3, and PMAT in behaviors relevant to psychiatric disorders is presented. Importantly, preclinical evidence revealing these transporters as targets for the development of novel therapeutics for psychiatric disorders is discussed.