Pancreatic cancer is still one of the most perilous malignant tumors with a very poor prognosis. Despite the progress in the diagnosis and treatment of pancreatic cancer, the overall 5-year survival rate after diagnosis is less than 10%. The pathogenesis of pancreatic cancer has not been fully clarified, but multiple factors are involved. The poor efficacy of traditional therapies for pancreatic cancer is mainly related to complex tumor microenvironment. In recent years, accumulating studies have demonstrated the role of autophagy and apoptosis triggered by endoplasmic reticulum stress in pancreatic cancer. In particular, unfolded protein response is activated by endoplasmic reticulum stress and plays an important role in the modulation of complex pancreatic tumor microenvironment. Here we summarize recent progress in our understanding of the role of unfolded protein response activated by endoplasmic reticulum stress in tumorigenesis of pancreatic cancer, and highlight the potential of the cascade of unfolded protein response as therapeutic target for pancreatic cancer.