Primary hepatocytes display a precipitous decline in phenotypic functions when cultured in a sandwich of extracellular matrix proteins (i.e. collagen, Matrigel), which severely limits the ability of these model systems to accurately predict clinical outcomes. Here, we describe a human liver model with precise microscale cyto-architecture and optimal stromal interactions (HepatoPac®) that displays high levels of liver-specific functions for up to 4 weeks in vitro and has been shown to improve predictions of clinical outcomes as compared to traditional approaches. HepatoPac has been miniaturized into 24- and 96-well industry-standard multi-well formats, and optimized for the screening of drug disposition and drug-induced liver injury. Toxicities of several hepatotoxins (i.e. Troglitazone, Tolcapone, Fialuridine) in HepatoPac under chronic dosing regimens (days to weeks) show concordance with pre-clinical and clinical findings. Transporter assays (uptake and efflux) can be performed in HepatoPac toward simultaneous assessment of the interplay of drug transport, metabolism and toxicity.