All pancreatic cell populations arise from the standard gut endoderm layer in developing embryos, requiring a regulatory gene network to originate and maintain endocrine lineages and endocrine function. The pancreatic organogenesis is regulated by the temporal expression of transcription factors and plays a diverse role in the specification, development, differentiation, maturation, and functional maintenance. Altered expression and activity of these transcription factors are often associated with diabetes mellitus. Recent advancements in the stem cells and invitro derived islets to treat diabetes mellitus has attracted a great deal of interest in the understanding of factors regulating the development, differentiation, and functions of islets including transcription factors. This review discusses the myriad of transcription factors regulating the development of the pancreas, differentiation of β-islets, and how these factors regulated in normal and disease states. Exploring these factors in such critical context and exogenous or endogenous expression of development and differentiation-specific transcription factors with improved epigenetic plasticity/signaling axis in diabetic milieu would useful for the development of β-cells from other cell sources.