Organoids and microphysiological systems represent two current approaches to reproduce organ function in vitro . These systems can potentially provide unbiased assays of function which are needed to understand the mechanism of action of environmental toxins. Culture models that replicate organ function and interactions among cell types and tissues move beyond existing screens that target individual pathways and provide a means to assay context-dependent function. The current state of organoid cultures and microphysiological systems is reviewed and applications discussed. While few studies have examined environmental pollutants, studies with drugs demonstrate the power of these systems to assess toxicity as well as mechanism of action. Strengths and limitations of organoids and microphysiological systems are reviewed and challenges are identified to produce suitable high capacity functional assays.