Ampullary cancer is a relatively rare cancer of the digestive tract. In contrast to pancreatic cancer, ampullary cancer is often curable if detected at an early stage. The evaluation and management of ampullary cancer is similar to, but distinct from, that of other pancreaticobiliary tumors. This manuscript will review the current evaluation, diagnosis, and therapy of patients with ampullary cancer. The diagnosis of ampullary cancer is complicated by its similar clinical presentation to pancreatic cancer as well as its nonspecific laboratory findings. Diagnostic modalities such as ERCP, EUS, and biopsy are necessary for differentiating the 2 cancers, and noninvasive imaging techniques such as MRI and CT may be used for tumor staging. Although pancreaticoduodenectomy is considered the primary curative surgical option, consensus guidelines regarding adjuvant and neoadjuvant chemoradiation therapies are lacking.