More physiologically and pathologically relevant preclinical human liver models are needed for drug liver liability assessment and liver disease modeling. While Drug-Induced Liver Injury (DILI) remains a major safety concern, several recent high-profile NAFLD/NASH clinical trial failures further highlight this critically unmet need. With the advances in 3D culture, we and others have demonstrated the usefulness of liver spheroids made from primary human hepatocytes (PHHs) as a novel tool for in vitro hepatotoxicity studies.