The kidney and liver secrete a diverse array of positively charged organic molecules, including many widely prescribed drugs. Although one characteristic of the suite of transporters that mediate this process is their (necessary) multiselectivity, it includes the potential for unwanted drug-drug interactions (DDIs) at the point of secretion, interactions that can influence a drug’s clinical or toxicological profile. In addition, interactions at the level of renal (and hepatic) drug transport can influence drug accumulation within these organs, with concomitant effects on drug toxicity. Thus, predicting the occurrence of DDIs is a major focus of work on OC transport. The cellular model of OC secretion by renal proximal tubule (RPT) cells, hepatocytes, and other barrier epithelia involves the sequential activity of an OC ‘entry step,’ from blood to cell across the basolateral membrane (BLM), via an electrogenic organic cation transporter; followed by an apical ‘exit step,’ from cell to the adjacent fluid-filled compartment (e.g., renal tubular filtrate or bile), mediated by electroneutral OC/H+ exchange. Whereas apical ‘exit’ appears to be dominated by one or more members of the MATE family of transporters (Multidrug And Toxin Extrusion; SLC2247), OC ‘entry’ is mediated by one or more members of the Organic Cation Transporter family (SLC22A). This presentation focuses on these OCTs, with particular emphasis on the following issues: (i) Site of OCT expression. OCT1 in humans is primarily expressed in the sinusoidal membrane of hepatocytes (with some in apical membrane of RPT cells and BLM of enterocytes). In rodents, Oct1 is expressed in BLM of RPT cells, as well as in the liver. OCT2 in humans and rodents is primarily expressed in BLM of RPT cells. In contrast, OCT3 has a very broad tissue distribution. (ii) Molecular/structural properties. The human OCTs (554-556 amino acids) have 12 transmembrane helices (TMHs) and a protein fold that includes N- and C-terminal halves of 6 TMHs each, separated by a large water-filled cleft (the substrate translocation pathway) with an extensive, putative binding surface. An extracellular loop between TMHs 1 and 2 influences OCT-OCT interaction, including formation of functional multimers. (iii) Energetics and kinetics. Although OCTs support electroneutral OC/OC exchange, the prominent physiological mode of operation is electrogenic uniport. Consequently, the inside negative membrane potential of RPT cells and hepatocytes is the principal driving force for OC+ entry. Transport follows Michaelis-Menten kinetics with apparent Km values that range from sub-μM to well above 1 mM. Substrates with low affinity frequently display comparatively large maximal rates, resulting in transport efficiencies (‘Vmax/Km’) that permit high flux even for ‘low affinity’ substrates. (iv) Selectivity. The OCTs typically transport molecules that share little in common structurally except cationic charge, modest hydrophobicity, and one or more hydrogen donor/acceptor sites. Although the several pharmacophores developed to define the structural determinants of ligand interaction with OCT1 and OCT2 generally include these features, their 3D locations differ, perhaps reflecting use of structurally distinct substrates as the marker of OCT transport activity, i.e., a consequence of ‘substrate-dependent’ ligand interactions. Consistent with this possibility, the kinetics of ligand interaction (of both substrates and inhibitors) include competitive, noncompetitive and mixed-type mechanisms. Taken with current views of OCT structure (see above), it is likely that ligand binding to OCTs involves a large surface with multiple interaction sites. (v) Regulation. The long cytoplasmic loop between TMHs 6 and 7 of all three OCTs contains multiple consensus phosphorylation sites potentially available for acute modulation of transport activity. Consistent with this observation, OCT1 and OCT2 respond to kinase activation (e.g., PKA and PKC), although there are substantial species differences in the resulting effect on transport. Sex steroids exert substantial influence on long-term expression of OCT2. (vi) Impact on drug clearance. Elimination of Oct1 and Oct2 in mice eliminates TEA secretion, and decreases its accumulation in kidney and liver, supporting the view that OCTs mediate the entry step in OC secretion. The common (~15%) OCT2 polymorphism, A270S, alters metformin transport and has been correlated with changes in metformin PD and PK. However, whereas elimination of Oct1/2 decreases metformin clearance and tissue accumulation in mice (as expected), metformin PD effects were not diminished, complicating the link between OCT activity and drug PD. It is clear that OCTs play a central role in drug clearance. But the field still falls short of the goal of predicting clinically relevant DDIs and the influence of genetic variation on OCT activity.