Significance: Type 1 diabetes (T1D) results from cell-mediated autoimmune destruction of insulin-secreting pancreatic beta cells (β-cells). In the context of T1D, the scarcity of organ donors has driven research to alternate sources of functionally competent, insulin-secreting β-cells as substitute for donor islets to meet the clinical need for transplantation therapy. Recent Advances: Experimental evidence of an inherent plasticity of pancreatic cells has fuelled interest in in vivo regeneration of β-cells. Transcriptional modulation and direct reprogramming of noninsulin secreting pancreatic α-cells to functionally mimic insulin-secreting β-cells is one of the promising avenues to the treatment of diabetes. Recent studies now show that adult progenitor and glucagon+ α-cells can be converted into β-like cells in vivo, as a result of specific activation of the Pax4 gene in α-cells and curing diabetes in preclinical models. Critical Issues: The challenge now is to understand the precise developmental transitions mediated by endocrine transcription factors and co-regulatory determinants responsible for pancreatic function and repair. Future Directions: Epigenetic-mediated regulation of transcription factor binding in pancreatic α-cells by specific drugs to direct reprogramming into functional insulin producing cells could be of potential innovative therapy for the treatment of T1D.