Drug transporters are now widely acknowledged as important determinants governing drug absorption, excretion, and, in many cases, extent of drug entry into target organs. There is also a greater appreciation that altered drug transporter function, whether due to genetic polymorphisms, drug-drug interactions, or environmental factors such as dietary constituents, can result in unexpected toxicity. Such effects are in part due to the interplay between various uptake and efflux transporters with overlapping functional capabilities that can manifest as marked interindividual variability in drug disposition in vivo. Here we review transporters of the solute carrier (SLC) and ATP-binding cassette (ABC) superfamilies considered to be of major importance in drug therapy and outline how understanding the expression, function, and genetic variation in such drug transporters will result in better strategies for optimal drug design and tissue targeting as well as reduce the risk for drug-drug interactions and adverse drug responses.