Periampullary cancers make up 5% of all gastrointestinal cancers. The complexity of the periampullary anatomy makes determination of the origin of some of these tumors difficult. However, advances in imaging have helped with diagnosis as well as defining the extent of the lesion and its potential resectability. For many of these tumors, surgery is the recommended treatment. However, endoscopic removal is being extended to different lesions with encouraging preliminary results. Improvements in overall prognosis for periampullary tumors will be limited until diagnosis can be established earlier in the course of the disease and adjuvant therapies become more effective.