Abstract: Recent advances in the expansion and directed pancreatogenic differentiation of human pluripotent stem cells (hPSCs) have intensified efforts to generate functional pancreatic islet cells, especially insulin-secreting β-cells, for cell therapies against diabetes. However, the consistent generation of glucose-responsive insulin-releasing cells remains challenging. In this article, we first ... read morepresent basic concepts of pancreatic organogenesis, which frequently serves as a basis for engineering differentiation regimens. Next, past and current efforts are critically discussed for the conversion of hPSCs along pancreatic cell lineages, including endocrine β-cells and α-cells, as well as exocrine cells with emphasis placed on the later stages of commitment. Finally, major challenges and future directions are examined, such as the identification of factors for in vivo maturation, large-scale culture and post processing systems, cell loss during differentiation, culture economics, efficiency, and efficacy and exosomes and miRNAs in pancreatic differentiation.