Ampullary cancers are rare, accounting for only 0.2% of gastrointestinal cancers and approximately 7% of all periampullary cancers. They arise from the ampullary complex, distal to the confluence of the common bile and pancreatic duct (Fig. 1). In contrast to other periampullary malignancies, true ampullary cancers present earlier in their disease course with symptoms that result from biliary obstruction. It is often difficult to distinguish primary ampullary cancers from other periampullary cancers preoperatively. In early stages, ampullary cancers are surgically treated, similar to pancreatic cancers, and typically with a pancreatico-duodenoectomy (or Whipple procedure). Because of their earlier presentation, resection rates for all patients are much higher than other periampullary carcinomas. Moreover, their prognosis tends to be better than those with other periampullary- and pancreatic-originating cancers. In patients with true ampullary cancer, there is very limited data to guide physicians on the choice of therapy, largely because of the rarity of the disease and the paucity of related research. Herein, we provide an overview of the biology, histology, current therapeutic strategies, and potential future therapies for carcinomas arising from the ampulla of Vater.