The biliary ductal system is necessary for digestion, absorption, and detoxification, with cholangiocytes playing a key role in immune regulation. Primary sclerosing cholangitis (PSC) is a chronic, immune-mediated cholangiopathy that affects the intrahepatic and extrahepatic bile ducts, and eventually leads to cirrhosis. It is strongly associated with inflammatory bowel disease (IBD), specifically ulcerative colitis. Many patients are asymptomatic but others can present with right upper quadrant pain, pruritus, and jaundice. Complications include cholangitis, portal hypertension and cholangiocarcinoma. Laboratory tests show elevated alkaline phosphatase, gamma-glutamyl transferase (GGT) with mildly increased aminotransferases and positive p-ANCA. MRCP is the gold standard for imaging which reveals the characteristic appearance of “beaded” bile ducts. There is no definitive treatment for PSC. Endoscopic intervention can be done for strictures but the progression of PSC often necessitates liver transplantation. A mimic of PSC is IgG4-related sclerosing cholangitis (IgG4-SC). It is a fibroinflammatory disorder characterized by IgG4+ plasma cell infiltration and fibrosis, involving B and T cell immune dysregulation. Elevated serum IgG4 with additional imaging and histology aids in its diagnosis. Glucocorticoids are first-line therapy, and rituximab may be used in refractory cases. It is important to distinguish between PSC and IgG4-SC for tailored approaches to treatment. Continued research is vital to advance targeted treatments for these autoimmune cholangiopathies.