Inhibition of enzyme activity at high substrate concentrations, so-called "substrate inhibition," is commonly observed and has been recognized in drug metabolism reactions since the last decade. Although the importance of such "atypical" kinetics in vivo remains poorly understood, a substrate with substrate inhibition kinetics has been shown to unconventionally alter the metabolism of other substrates. In recent years, it is becoming increasingly evident that the mechanisms for substrate inhibition are highly complex, which are possibly contributed by multiple (at least two) binding sites within the enzyme protein, the formation of a ternary dead-end enzyme complex, and/or the ligand-induced changes in enzyme conformation. This review primarily discusses the mechanisms for substrate inhibition displayed by the important drug-metabolizing enzymes, such as cytochrome p450s, UDP-glucuronyltransferases, and sulfotransferases. Kinetic modeling of substrate inhibition in the absence or presence of a modifier is another central issue in this review because of its importance in the determination of kinetic parameters and in vitro/in vivo predictions.