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Background: Over the last decades, various approaches have been explored to restore sufficient β-cell mass in diabetic patients. Stem cells are certainly an attractive source of new β-cells, but an alternative option is to induce the endogenous regeneration of these cells. Scope of Review: Since the exocrine and endocrine pancreatic glands have a common origin and a continuous crosstalk unites the two, we believe that analyzing the mechanisms that induce pancreatic regeneration in different conditions could further advance our knowledge in the field. In this review, we summarize the latest evidence on physiological and pathological conditions associated with the regulation of pancreas regeneration and proliferation, as well as the complex and coordinated signaling cascade mediating cell growth. Major conclusions: Unraveling the mechanisms involved in intracellular signaling and regulation of pancreatic cell proliferation and regeneration may inspire future investigations to discover potential strategies to cure diabetes.