Pancreatic cancers exhibit a unique dependence on autophagy for tumor growth. In this study, researchers found that pancreatic cancer primary tumors and cell lines show elevated autophagy under basal conditions. Genetic or pharmacologic inhibition of autophagy leads to increased reactive oxygen species (ROS), elevated DNA damage, and a metabolic defect leading to decreased mitochondrial oxidative phosphorylation. These changes ultimately result in significant growth suppression of pancreatic cancer cells in vitro. Importantly, inhibition of autophagy by genetic means or chloroquine treatment leads to robust tumor regression and prolonged survival in pancreatic cancer xenografts and genetic mouse models. These findings suggest that autophagy is required for the tumorigenic growth of pancreatic cancers and that drugs that inactivate this process may have a unique clinical utility in treating pancreatic cancers and other malignancies with a similar dependence on autophagy. Chloroquine and its derivatives are potent inhibitors of autophagy and have been used safely in human patients for various purposes, making them immediately translatable to the treatment of pancreatic cancer patients.Pancreatic cancers exhibit a unique dependence on autophagy for tumor growth. In this study, researchers found that pancreatic cancer primary tumors and cell lines show elevated autophagy under basal conditions. Genetic or pharmacologic inhibition of autophagy leads to increased reactive oxygen species (ROS), elevated DNA damage, and a metabolic defect leading to decreased mitochondrial oxidative phosphorylation. These changes ultimately result in significant growth suppression of pancreatic cancer cells in vitro. Importantly, inhibition of autophagy by genetic means or chloroquine treatment leads to robust tumor regression and prolonged survival in pancreatic cancer xenografts and genetic mouse models. These findings suggest that autophagy is required for the tumorigenic growth of pancreatic cancers and that drugs that inactivate this process may have a unique clinical utility in treating pancreatic cancers and other malignancies with a similar dependence on autophagy. Chloroquine and its derivatives are potent inhibitors of autophagy and have been used safely in human patients for various purposes, making them immediately translatable to the treatment of pancreatic cancer patients.