Applications of pluripotent stem cells in cell therapy and disease modeling require robust differentiation methods for the cells of interest. We have shown that insight into the extracellular cues that control the transcriptional machinery involved in cell fate decisions can be translated into more reliable and cost-effective differentiation strategies. Here, we will present new data on how iPSC modeling of monogenetic forms of diabetes reveals the primary disease-causing event. We also identify new personalized therapeutic options targeted at the primary cause of the disease that may delay or even prevent the onset of disease.