Approaches that induce the proliferation of insulin-producing pancreatic beta cells hold promising therapeutic potential to treat both insulin-dependent and insulin-independent diabetes. However, the factors that regulate beta cell proliferation in human remain unknown, and drugs that control proper beta cell mass are in high demand. Here, we aimed to identify small molecules that induce the proliferation of pancreatic beta cells as a novel therapy to treat diabetes. With this aim, we focused on c-Myc gene, which is an essential driver of proliferation in beta cells, and generated multiple human iPSC lines constitutively expressing a luciferase reporter under the control of human c-Myc promoter. Then, we developed a luciferase-based high-throughput screening (HTS) system to detect small molecules that directly or indirectly enhance the activity of c-Myc promoter in beta cells derived from the human iPSCs. Screens of 5,120 compounds using this system identified several candidates with enhanced c-Myc promoter activity, and we confirmed that one compound promotes human iPSC-derived beta cell proliferation. We are currently examining the mechanisms of action of the compound. Our finding could contribute to the identification of novel targets for increasing beta cell mass.