It should be fairly clear that the evaluation of pancreatic duct strictures is complex. Short of surgical resection, there is no gold standard that will provide an etiological diagnosis unless cancer is found on a biopsy specimen. To complicate matters further, much of the literature was generated in reference to differentiating between pancreatic cancer and pancreatitis. Using the same data to evaluate the patient with a pancreatic duct stricture may not be appropriate because the clinical scenario may not be comparable. Bearing these shortcomings in mind, however, a thoughtful history combined with the judicious use of abdominal imaging, ERCP, and the biopsy techniques discussed will lead to a clinical diagnosis that usually will prove to be correct in most cases. The role of tumor markers in patients with pancreatic duct strictures is still being defined. Although no tumor marker has proved especially helpful so far, the potential exists that a more useful one is just over the horizon. In situations in which the diagnosis remains uncertain, exploratory laparotomy in an appropriate surgical candidate by an experienced pancreatic surgeon will provide a definitive diagnosis in almost all cases.