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The specific cell of origin responsible for generating pancreatic intraepithelial neoplasia and pancreatic ductal adenocarcinoma remains unknown. During development, epithelial stem cells within embryonic pancreatic epithelium give riseto mature acinar, ductal, and islet elements. Emerging evidence suggests that cells with precursor potential also exist within adult pancreas, resulting in significant developmental plasticity among both endocrine and exocrine cell types. In this review, the contribution of developmental plasticity in initiating pancreatic metaplasia and neoplasia is considered, and evidence supporting a role for epithelial stem cells in pancreatic cancer is discussed.