Time-dependent inhibition (TDI) of CYP refers to a change in potency during an in vitro incubation or dosing period in vivo. Potential mechanisms include the formation of inhibitory metabolites and mechanism-based inhibition (MBI). In vitro experiments are configured to assess TDI and MBI is inferred, at least initially. MBI is more profound after multiple-dosing and the recovery period is independent of continued drug exposure. Advances in in vitro-in vivo extrapolations for competitive inhibition and the potential relationship between MBI and reactive metabolite-mediated toxicity, have redirected emphasis to CYP TDI. In contrast, with reversible inhibition, strategies for projecting the risks from TDI are less developed and the traditional I/KI model often yields a dramatic underprediction. This review explores the contribution of TDI to drug-drug interactions and idiosyncratic drug toxicity.