With the dramatic change underway in the process of drug discovery and Development it has become increasingly important to define, both qualitatively and quantitatively, the dispositional features of new chemical entities (NCEs) as early in the process as possible. To that end strategies have emerged that are designed to enable reasonable predictions about a NCEs absorption from the gastrointestinal tract, systemic bioavailability and likelihood for significant pre-systemic clearance, character of metabolic processing both within the gastrointestinal tract and the liver, in vivo pharmacokinetics (PK), and likelihood for clinically significant interactions with other drugs. To some extent these strategies have embraced interspecies allometric scaling in which findings in animals are extrapolated to predict outcomes in humans. However, a greater emphasis in recent years has been placed on predicting human PK and the likelihood of clinically significant drug-drug interactions for NCEs solely from in vitro experiments. These general strategies have been methodologically streamlined so that hundreds or even thousands of experiments on a given NCE can be conducted within several days. Dispositional data from these pre-clinical experiments is useful for rapidly identifying potential marketing advantages for NCEs, and for screening out those substances that should not be placed into more expensive and labor-intensive animal experiments or brought to clinical trial. The key issue in these strategies is the accuracy with which pre-clinical findings predict clinical outcomes. Based largely on retrospective analyses the current state of the art exhibits a high percentage of useful predictions. However, there are many examples in which the prediction of either human PK or clinical drug-drug interactions from pre-clinical data has failed. The reasons for inaccurate predictions are manifold, and may include the actual in vitro methodology used, inappropriate model selection, and errant scale-up factors. Additionally, in vitro methods may fail to account for complex hepatobiliary processing including transport phenomena and Phase II metabolism. Progress has been made in establishing humanized methodologies that accurately describe these processes, with a view toward reconstituting the contributions of each into a more complex and accurate depiction and prediction of in vivo PK and drug-interaction potential.