Total pancreatectomy with intrahepatic autoislet transplantation (TP/IAT) is a definitive treatment for relentlessly painful chronic pancreatitis. Pain relief is reported to be achieved in approximately 80% of patients. Overall, 30% to 40% achieve insulin independence, and 70% of recipients remain insulin independent for > 2 years, sometimes longer if > 300 000 islets are successfully transplanted. Yet, this approach to chronic pancreatitis is underemphasized in the general medical and surgical literature and vastly underused in the United States. This review emphasizes the history and metabolic outcomes of TP/IAT and considers its usefulness in the context of other, more frequently used approaches, such as operative intervention with partial pancreatectomy and/or lateral pancreaticojejunostomy (Puestow procedure), as well as endoscopic retrograde cholangiopancreatography with pancreatic duct modification and stent placement. Distal pancreatectomy and Puestow procedures compromise isolation of islet mass, and adversely affect islet autotransplant outcomes. Therefore, when endoscopic measures fail to relieve pain in severe chronic pancreatitis, we recommend early intervention with TP/IAT.