Pancreatic adenocarcinoma is a major cause of cancer death in the United States. Most cases are sporadic and are discovered at late stage when they are not curable by surgery. Information about the molecular biology of pancreatic adenocarcinoma has increased significantly in the last five years with the identification of alterations in the K-ras proto-oncogene and the p16INK4a, p53, FHIT, and DPC4 tumor suppressor genes in a high percentage of tumors. Pancreatic adenocarcinoma is not homogeneous genetically, however, and other genes are clearly involved in some sporadic and heritable tumors. This review summarizes recent data relating to the molecular biology of pancreatic adenocarcinoma with emphasis on features which may be of clinical significance for diagnosis and/or therapy. Molecular genetic alterations that disturb cell cycle regulation in tumor cells can affect their response to chemotherapeutic agents and radiation and many of these genes are targeted in pancreatic adenocarcinoma. Knowledge of these genetic alterations in individual tumors may allow selection of optimal therapeutic strategies for individual patients. Furthermore, molecular detection of oncogene and tumor suppressor gene mutations may find application as screening tests for pancreatic adenocarcinoma at least in high risk populations. Biological therapy aimed at specific oncogenes and tumor suppressor gene replacement therapy protocols for pancreatic adenocarcinoma are beginning and may offer promise in the future.