Pancreatic cancer is one of the most aggressive and devastating human malignancies. Despite new knowledge in the molecular profile of pancreatic cancer and its precursor lesions, survival rates have changed very little over the last 40 years. Therefore, a better understanding of the detailed mechanisms underlying the pathogenesis of this disease is critical if we expect to develop new and effective strategies for prevention, early diagnosis and treatment of pancreatic cancer. The review herein focuses on a distinctive signaling pathway, the Notch pathway, which has recently been associated with carcinogenesis, including pancreatic cancer. It is aimed at summarizing key results which support a role for this pathway in the initiation, progression and maintenance of pancreatic cancer as a rationale for targeting and inhibiting this pathway in pancreatic cancer patients.