Despite scientific efforts and significant progress in understanding the basic cellular event in pancreatic adenocarcinoma (PA), survival rates have not changed much during the last 20 years. Prognosis in pancreatic cancer remains unsatisfactory due to its late clinical presentation, low surgical resectability rates, and resistance to chemotherapy. Novel therapeutic strategies are needed in order to improve the prognosis of patients with PA. Improvement of our knowledge of the molecular biology of pancreatic cancer may have important clinical implications in pancreatic cancer risk assessment, early diagnosis, and management. In human pancreatic cancer, a specific sequence of oncogene and tumor suppressor gene alterations is observed, including K-ras, HER-2/neu, p16, p53, and DPC4. The prevalence of these genetic alterations rises with increasing severity of dysplasia of the ductal mucosal lesions. Drugs that target these molecular abnormalities hold great promise for PA treatment in the near future. The focus of this review is to evaluate the gene mutations in pancreatic cancer, with emphasis on those studies that are most important to the clinical practice. Our review also summarizes current aspects of PA treatment and the differential diagnosis of pancreatic cancer and chronic pancreatitis.