Context .- Immunoglobulin G4 (IgG4)-related disease is a systemic fibroinflammatory disease capable of affecting virtually any organ. Although the pancreas and hepatobiliary system are commonly affected, involvement of the tubular gut is unusual. The pancreatic manifestations of this disease (autoimmune pancreatitis) often mimic pancreatic carcinoma, whereas the hepatobiliary manifestations are mistaken for cholangiocarcinoma or primary sclerosing cholangitis. The characteristic histologic features include a dense lymphoplasmacytic infiltrate, storiform-type fibrosis, and obliterative phlebitis. An increase in IgG4(+) plasma cells and an IgG4 to IgG ratio of more than 40% are considered obligatory components of the diagnostic algorithm. Objective .- To review the challenges associated with the diagnosis of IgG4-related disease of the gastrointestinal tract. Data Sources .- A review of pertinent literature, along with the author's personal experience, based on institutional and consultation materials. Conclusion .- The complete spectrum of histologic changes is seldom captured in a biopsy specimen, and thus, the histopathology findings are best interpreted within the overall clinical context. Increased IgG4(+) plasma cells are identified in a variety of benign and malignant diseases of the gastrointestinal tract.