Drug-induced liver injury (DILI) remains a major cause of drug attrition during drug discovery and development because animal models and existing in vitro models often do not predict outcome in humans. There is a significant need for more predictive models for DILI. These models must include the relevant cell types that are representative of in vivo metabolic capabilities, provide the ability to conduct long-term maintenance of cell viability to enable repeated drug exposures, and include the capability to demonstrate the diverse mechanisms of DILI. Advanced engineering fabrication techniques were applied to achieve a high level of control over the liver tissue microenvironment. The Liver-Chip incorporates relevant cell-extra cellular matrix (ECM) interactions, a hepatocyte and liver sinusoidal endothelial cell interface, along with relevant cyto-architecture and physiological flow. In addition to the human Liver-Chip, rat and dog models were developed to enable characterization of species differences with respect to pharmacokinetics, toxicity, and mechanism of action.