Due to significant differences across species in liver pathways, models of the human liver are used to screen for potential efficacy and/or toxicity of candidate compounds. Such models serve to complement and reduce the number of animals used in studies required by regulatory agencies. However, once isolated from the liver’s microenvironment, primary hepatocytes rapidly (hours to days) lose phenotypic functions under culture formats that rely exclusively on homogenous extracellular matrix (i.e. collagen) manipulations. The liver microenvironment in vivo is more complex with cues such as diverse extracellular matrices, tight interactions between hepatocytes and stromal cells, and a precise cellular organization (i.e. architecture). Here, I will discuss our use of semiconductor-driven microfabrication tools and co-culture techniques for building a high fidelity and miniaturized liver model called micropatterned co-cultures (MPCCs). In particular, design principles underlying the development of MPCCs will be discussed followed by functional characterization data sets that have been acquired on MPCCs created using hepatocytes from both human and animal sources. Finally, I will discuss emerging applications of MPCCs and their continued evolution into predicting clinical outcomes with greater sensitivity. In the future, engineered human liver platforms can significantly reduce drug attrition to lower the cost of drug development and prevent harm to patients in the clinic.