Recently, metabolic drug-drug interactions (M-DDI) have raised some high-profile problems in drug development resulting in restricted use, withdrawal or non-approval by regulatory agencies. The use of in vitro technologies to evaluate the potential for M-DDI has become routine in the drug development process. Nevertheless, in the absence of an integrated approach, their interpretation and value remains the subject of debate, and the vital distinction between a useful “simulation” and a precise “prediction” is not often appreciated. Various in silico software are now available for the simulation of M-DDI. However, a concerted effort by the industry is necessary to evaluate their use. The FDA has recently emphasized the importance of such collaboration to improve the crucial path to development of new drugs. In silico simulation of M-DDI has the potential to add significant value to this process.