Total pancreatectomy with islet autotransplantation (TPIAT) has traditionally been employed for patients with chronic pancreatitis, but its use has increasingly expanded to include specific cases of pancreatic neoplasms. The Milan protocol has systematically extended TPIAT indications to both malignant and nonmalignant pancreatic lesions, provided that multifocality is excluded preoperatively and confirmed with negative intraoperative frozen section margins. This procedure is also being explored for patients undergoing salvage completion pancreatectomy after severe postoperative pancreatic fistula (POPF) following pancreaticoduodenectomy, as well as for those at high risk of developing POPF, offering a potential alternative to pancreaticoduodenectomy. Recent randomized studies have demonstrated that TPIAT is both feasible and safe in these contexts, with metabolic outcomes similar to those observed in patients with chronic pancreatitis. However, the application of TPIAT for intraductal papillary mucinous neoplasms (IPMNs) remains limited, with scarce data and no prospective trials specifically addressing this indication. The increasing detection of IPMNs, particularly as incidental findings, and their potential for multifocality underscore the need for further investigation into the role of TPIAT in this setting. Despite TPIAT’s relatively niche status for pancreatic neoplasms, largely due to the limited availability of islet processing centers, existing evidence supports its use in carefully selected cases. Although concerns regarding tumor spread after TPIAT in oncologic contexts persist, available data suggest that the procedure can be performed safely, offering a significant improvement in the quality of life for patients following total pancreatectomy. In conclusion, while TPIAT for pancreatic neoplasms remains an emerging application, it holds promise as a strategy to address diabetes following pancreatectomy. As the understanding of its safety and efficacy in this context continues to evolve, further research is needed to clarify its role, particularly in the management of IPMNs and other pancreatic malignancies.