Pancreatic cancer is an aggressive malignancy with poor survival and high mortality rate with 250 000 deaths per year worldwide. The unique pancreatic cancer microenvironment serves as a major obstacle in the effective treatment of this malignancy. The microenvironment consists not only of pancreatic ductal adenocarcinoma cells but also comprises cells of pancreatic cancer stellate, vascular, and immune origin combined with a dense extracellular matrix containing collagen. The aforementioned pathology leads to an increased intratumor pressure combined with an erratic vascular proliferation within the tumor causing hypoxia and decreased drug delivery. This has led both scientists and clinicians to develop and study drugs with unique mechanisms of action to target the pancreatic cancer microenvironment. Herein, we discuss the pancreatic cancer hypoxic microenvironment, development of hypoxia-activated prodrugs, and results of trials utilizing those drugs to target pancreatic cancer.