The organic cation transport systems were initially recognized in studies of renal elimination. A variety of endogenous and exogenous compounds that are harmful to the body are eliminated from the kidney via glomerular filtration and/or active tubular secretion. Among those compounds are polar organic cations that require a transporter-mediated process to cross cellular membrane and be eventually excreted into the urine. The organic cation transport systems in the kidney have been recognized for several decades. Following the insight gained from the kidney, organic cation transporters (OCTs) have also been characterized in other tissues. In particular, the OCTs in the liver and in the intestine have been proposed as important determinants of drug absorption and disposition. Over the past several decades, the mechanisms of organic cation transport have been extensively characterized using in vivo models, ex vivo organ perfusions, in vitro tissue preparations and cell lines. In particular, the molecular cloning and characterization of OCTs have remarkably increased our knowledge of this important subfamily of solute carriers. In this article, we first review the molecular cloning and characterization of OCTs. We will then describe their transport mechanisms, tissue distribution and localization, and their specificity of interaction with organic cations. Regulatory mechanisms and genetic animal models will be reviewed as they provide the most important insight on this class of transporters in recent years. Finally, we will summarize genetic variation in human OCT genes and raise clinical perspectives on these important transporters.