Adenocarcinoma of the pancreas is the fourth leading cause of cancer death in the United States. Because of the poor therapeutic responsiveness of pancreatic cancer to surgery, chemotherapy, and radiation therapy, survival beyond five years is rare with median survival less than six months. K-ras mutations have been identified in up to 95% of pancreatic cancers, implying their critical role in the molecular pathogenesis. Ras overexpression leads to increased production of reactive oxygen species (ROS) through activation of the NADPH oxidase system resulting in downstream propagation of mitogenic signaling leading to cell growth and tumor progression. The superoxide dismutases (SOD) convert O2 .- into H2O2. Extracellular SOD (ECSOD) is the only isoform of SOD that is expressed extracellularly, manganese-containing superoxide dismutase (MnSOD) is localized in the mitochondria, and copper- and zinc-containing superoxide dismutase (CuZnSOD) in the cytoplasm. The catalases and peroxidases convert H2O2 into water. Catalase is located in peroxisomes and cytoplasm and peroxidases are in many subcellular compartments. Antioxidant enzymes that scavenge specific ROS have inhibited the in vitro and in vivo growth of pancreatic cancer. Additionally, food-derived polyphenols, which may act by scavenging reactive oxygen species, can also inhibit pancreatic cancer growth. This review will concentrate on the sophisticated antioxidant defense system, which may shed insight into the etiology, diagnosis, and treatment of pancreatic cancer.