Accurate prediction of human drug safety remains a major challenge for drug development. Species-difference in drug toxicity represents a main reason for the difficulty in the prediction of human drug toxicity with nonhuman animal models. A combined in vitro-in vivo strategy (IVIVS), using human-based in vitro experimental systems to derive humanspecific information, and animal systems for in vivo variables, may lead to a more accurate prediction of human in vivo drug toxicity. The success of IVIVS requires in vitro models with human-specific drug metabolism, appropriate target cell populations, and relevant endpoints. A novel theory, the Target Cell Initiation Theory for drug-induced organ failure (TACIT), is proposed to support the IVIVS. Based on TACIT, toxicity that requires chronic administration and multiple secondary changes may be defined by the evaluation of changes in target cells that initiate the cascade of secondary events. A novel in vitro experimental system, the Integrated Discrete Multiple Organ Co-culture (IdMOC) system, which allows the evaluation of multiple organ toxicity under conditions allowing multiple organ interactions, is described as a promising technology.