The most common method for estimating a drug's in vivo clearance from in vitro data has involved using the classical Michaelis-Menten model to describe the observed in vitro data and from this estimate intrinsic clearance. This process assumes that the drug obeys standard enzyme kinetics that can be described by this model. However, the observation of atypical enzyme kinetics, particularly involving cytochrome P450 enzymes, has become relatively common, and occurrences have been reported with virtually all of the cytochrome P450 isoforms. Since predictions of a drug's in vivo clearance are made based on kinetic parameters observed during in vitro experiments (in vitro estimated intrinsic clearance), mis-identification of the drug's kinetic profile can lead to inaccurate predictions of intrinsic clearance. In addition to these potential ramifications of in vitro-in vivo predictions, information is becoming available concerning the in vivo implications of drugs that exhibit atypical kinetic profiles. This review will discuss the various types of atypical kinetic profiles that may be observed during in vitro experiments, hypotheses for why they may occur, examples of how a drug's intrinsic clearance may be mis-estimated when atypical kinetics are incorrectly assessed, and the potential ramifications of these issues for prediction of drug interactions. Furthermore, potential, artifactual causes of atypical kinetic phenomena will be described.