IgG4-related sclerosing cholangitis (IgG4-SC) is an immune-mediated disease of the biliary tract that mimics cancer such as cholangiocarcinoma or primary sclerosing cholangitis. Pathogenesis involves the influence of environmental factors such as industrial fumes, dust, gases, fumes and asbestos together with dysregulated immunity, including CD4+ T-cell response (Th2, Tfh, Tregs), activated B-cells and fibrosis. Diagnosis requires a multimodal approach: elevated serum IgG4 (>2× upper limit of normal suggestive, >4× highly specific), IgG4/IgG1 ratio >0.24, involvement of other organs (especially autoimmune pancreatitis type 1), histopathology and rapid response to corticosteroids. The discovered IgG4/IgG1 autoantibodies against annexin A11 and laminin 511-E8 point to direct pathogenic mechanisms. Although steroids produce a high initial response, relapse occurs in 30–50% of patients, so maintenance therapy with azathioprine, mycophenolate mofetil, or rituximab is used; inebilizumab is a new option. A high degree of suspicion is necessary in obstructive jaundice and biliary strictures, with an emphasis on validating biomarkers such as circulating plasmablasts to prevent relapses and fibrosis.