Hypoxia inducible factors (HIFs) are critical regulators of the response to oxygen deficiency by activating target genes involved in a variety of biological functions. HIFs have been implicated in the pathophysiology of numerous pathologies including cancer. Patients with mutations in the von Hippel-Lindau (VHL) gene, an essential regulator of HIF activity, develop tumors in several organs including the pancreas. Previous functional studies of HIF activation in the pancreas have used Vhlh (the murine homolog of VHL) deficient mice. However, the role of each specific HIF transcription factors in the pancreas has not been thoroughly examined. We derived mice that constitutively express a normoxia-stable form of HIF2α in the pancreas. Activation of HIF2α in the pancreas severely impairs postnatal exocrine pancreas. Mice with pancreas-specific activation of HIF2α develop histological features reminiscent of pancreatitis including loss of acinar cells, ductal dilation and fibrosis. Moreover, we provide evidence that signaling pathways important for acinar cell homeostasis are altered in HIF2α-overexpressing pancreata.