Pancreatic cancer, like most other cancers, is fundamentally caused by mutations in specific genes. Many of the genes targeted in pancreatic cancer have been identified in the past decade, and an understanding of these genes and their function has helped identify familial forms of pancreatic cancer, define the precursor lesions from which invasive pancreatic cancers arise, and will soon lead to gene-specific therapies for this disease. This article reviews the tumor-suppressor genes, oncogenes, and DNA repair genes targeted in pancreatic cancer, and presents clinical applications based on our understanding of the genetic basis of pancreatic cancer.