Hepatic elimination is a function of the interplay between different processes such as sinusoidal uptake, intracellular metabolism, canalicular (biliary) secretion, and sinusoidal efflux. In this review, we outline how drugs can be classified according to their in vitro determined clearance mechanisms using the extended clearance model as a reference. The approach enables the determination of the rate-determining hepatic clearance step. Some successful applications will be highlighted, together with a discussion on the major consequences for the pharmacokinetics and the drug-drug interaction potential of drugs. Special emphasize is put on the role of passive permeability and active transport processes in hepatic elimination.