Species differences in drug metabolism present two challenges that may confound the nonclinical safety assessment of candidate drugs. The first challenge is encountered when metabolites are formed uniquely or disproportionately in humans. Another challenge is understanding the human relevance of toxicities associated with metabolites formed uniquely or disproportionately in a nonclinical species. One potential approach to minimize the impact of metabolite related challenges is to consider genetically engineered mouse models that express human P450 enzymes. Human P450 expressing mouse models may have the ability to generate major human metabolites and eliminate or reduce the formation of mouse specific metabolites. Prior to determining the utility of any particular model, it is important to qualify by characterizing protein expression, establishing whether the model generates an in vivo metabolite profile more closely related to that of humans than the wild-type mouse, verifying genetic stability, and evaluating animal health. When compared to the current strategy for handling metabolite challenges (i.e., direct administration of metabolite), identifying an appropriate human P450 expressing model could provide a number of benefits. Such benefits include improved scientific relevance of the evaluation, decreased resource needs, and a possible reduction in the number of animals used. These benefits may ultimately improve the quality and speed by which promising new drug candidates are developed and delivered to patients.