The classification of precursor lesions arising in the ampullary region and in the intrapancreatic biliary tract has recently evolved. It largely includes adenomas, papillary-tubular neoplasms of the ampulla and intrapancreatic bile duct, and flat dysplasia/biliary intraepithelial neoplasia (BiIIN). Ampullary adenomas (AA) arise from the duodenal surface of the ampulla. Exophytic/tumoural neoplastic precursor lesions occurring within the ampullary channel are designated intraampullary papillary-tubular neoplasms (IAPNs), and their counterparts within the bile ducts are called intraductal papillary neoplasms of the bile duct (IPNBs). While AAs are usually intestinal type, IAPNs and IPNBs have different phenotypes, including pancreatobiliary, intestinal, gastric, oncocytic, and mixed types. IAPNs and IPNBs have a high incidence of high grade dysplasia and associated invasive carcinoma. Non-invasive and minimally invasive papillary neoplasms have a much better prognosis than conventional carcinomas. BiIIN is presently categorized as BiIIN-1, BiIIN-2 and BiIIN-3. BiIIN can be difficult to distinguish from reactive atypia. The role of immunohistochemistry and FISH studies in the diagnostic evaluation of early neoplastic lesions is discussed.