1. Various molecular mechanisms underlie the action of inhibitors of xenobiotic-metabolizing enzymes acting upon the enzyme itself and not elsewhere. 2. The activity of directly acting inhibitors is due to the compounds themselves rather than to metabolic intermediates thereof. When the enzyme's ground state is the target, competitive or non-competitive inhibition can be seen, depending on a number of factors. 3. Some inhibitors are transition-state analogues and bind slowly but with high affinity to the enzyme. Inhibition may be due to the compound itself and/or a metabolic intermediate. 4. Mechanism-based inhibitors are those which act via an in situ generated metabolic intermediate that can bind reversibly or irreversibly to the enzyme. 5. These various mechanisms are exemplified and discussed in terms of selectivity and reversibility.