Assessment of drug–liver interactions is an integral part of predicting the safety profile of new drugs. Existing model systems range from in vitro cell culture models to FDA-mandated animal tests. Data from these models often fail, however, to predict human liver toxicity, resulting in costly failures of clinical trials. In vitro screens based on cultured hepatocytes are now commonly used in early stages of development, but many toxic responses in vivo seem to be mediated by a complex interplay among several different cell types. We discuss some of the evolving trends in liver cell culture systems applied to drug safety assessment and describe an experimental model that captures complex liver physiology through incorporation of heterotypic cell–cell interactions, 3D architecture and perfused flow. We demonstrate how heterotypic interactions in this system can be manipulated to recreate an inflammatory environment and apply the model to test compounds that potentially exhibit idiosyncratic drug toxicity. Finally, we provide a perspective on how the range of existing and emerging in vitro liver culture approaches, from simple to complex, might serve needs across the range of stages in drug discovery and development, including applications in molecular therapeutics.