Organic cation transporters are critical in drug absorption, targeting, and disposition. It has become increasingly clear that multiple mechanisms are involved in organic cation transport in the key tissues responsible for drug absorption and disposition: the kidney, liver, and intestine. In this review, we discuss current models of transepithelial flux of organic cations in these three tissues. Particular emphasis is placed on the more recent molecular studies that have paved the way for a more complete understanding of the physiological and pharmacological roles of the organic cation transporters. Such information is essential in predicting pharmacokinetics and pharmacodynamics and in the design and development of cationic drugs.