Plasma membrane transporters on neuronal and glial membranes sustain chemical signaling at synapses through neurotransmitter precursor and nutrient uptake and by efficient clearance of neurotransmitters. The biogenic amine transporters that inactivate serotonin, dopamine and norepinephrine are particularly important drug targets as these molecules interact with multiple psychoactive agents including cocaine, amphetamines and antidepressants. Recent studies have revealed the presence of complex regulatory mechanisms that control the trafficking and catalytic activity of these transporter proteins, mediated by interactions with transporter-associated proteins that include kinases and phosphatases as well as proteins that help localize transporters to defined membrane domains. The pathophysiological significance of biogenic amine transporter dysfunction has begun to be elucidated through analysis of rare, functional genetic variants associated with brain disorders previously suggested to arise from altered serotonin, dopamine and norepinephrine signaling, including attention-deficit, hyperactivity disorder (ADHD), bipolar disorder, autism, and obsessive-compulsive disorder (OCD). Cellular phenotypes of transporter alleles include both loss and gain of function, anamolous transporter reversal and disrupted transporter regulation through cell signaling pathways.