Recombinantly expressed human cytochromes P450 (rhCYPs) have been underused for the prediction of human drug clearance (CL). Differences in intrinsic activity (per unit CYP) between rhCYP and human liver enzymes complicate the issue and these discrepancies have not been investigated systematically. We define intersystem extrapolation factors (ISEFs) that allow the use of rhCYP data for the in vitro-in vivo extrapolation of human drug CL and the variance that is associated with interindividual variation of CYP abundance due to genetic and environmental effects. A large database (n = 451) of metabolic stability data has been compiled and used to derive ISEFs for the most commonly used expression systems and CYP enzymes. Statistical models were constructed for the ISEFs to determine major covariates in order to optimize experimental design to increase prediction accuracy. Suggestions have been made for the conduct of future studies using rhCYP to predict human drug clearance.