The individual response to a drug in terms of drug efficacy and toxicity is highly variable; this represents a major problem in clinical practice. Potential causes for such variability include pathogenesis and severity of the disease being treated, drug interactions, patient age, nutritional status, renal and liver function and concomitant illness. Inherited differences in drug metabolism and genetic polymorphism of targets of drug therapy can have even greater influence on the efficacy and toxicity of medications. We will discuss the role of drug transporters (organic anion transporting polypeptides and Pgp), drug-related gene polymorphisms and pathologies, renal function and drug metabolism in a very special patient population, the newborn. Reliable predictions of drug pharmacokinetics in the newborn, derived from an understanding of the transport mechanisms, should allow therapeutic agents to be used more safely in this special population.