Abstract The effective discovery of new drugs as therapeutic agents remains a major challenge. Only 10% of Phase I developed compounds will eventually become approved therapies thus, the need for a productive drug development pipeline that counters the high financial burden coupled with low productivities. By increasing the number of compounds that can be tested while decreasing reagent consumption, advance microscale technologies have been useful tools to perform high-throughput screening in a cost-effective manner. Moreover, stem cell-based microscale platforms, with special interest in patient specific human-induced pluripotent stem cells, prompt a phenotypic drug discovery that allows the potential stratification drug response. In this chapter, we outline several microscale HTS approaches that have been employed in the regenerative medicine field, while given examples of specific studies employing stem cells and derived progeny for screening drug compounds and microenvironmental cues influencing cell behavior.