Chemotherapy and immunotherapy for pancreatic ductal adenocarcinoma (PDAC) have limited success. One reason for this is thought to be the cancer microenvironment surrounding PDAC. Hypoxia is a feature of the cancer microenvironment. Under hypoxia, different various molecules and signaling pathways are activated compared with normoxia. To develop a new effective therapeutic strategy for PDAC, we need to target these hypoxic conditions to overcome PDAC. To inhibit the malignant phenotype, the cellular changes that occur under hypoxia should be elucidated. Various molecules and signaling that are activated by hypoxia may contribute to the induction of malignant phenotypes of PDAC such as proliferation, invasion, tumorigenesis, chemosensitivity, and autophagy. If we can develop therapeutic approaches to target one of these molecules or signaling pathways, we may proceed to the next therapeutic step of successfully treating refractory PDAC.