Selecting appropriate candidates for total pancreatectomy and islet autotransplant (TPIAT) is a complex process. The TPIAT procedure is distinctive for several reasons, including the requirement for an experienced surgeon, a specialized islet cell isolation facility, and a committed multidisciplinary team. Islet autotransplantation does not necessitate immunosuppression, but perioperative morbidity remains significant (up to 60%). Patients being considered for TPIAT are best evaluated through a multidisciplinary team approach involving experts in a variety of specialties, utilizing an organized patient-specific treatment algorithm, with care tailored to the individual’s needs. The optimal time point for surgery is after issues with lifestyle related to pain or recurrent acute pancreatitis have developed, but before long-term complications from chronic pain arise. Multiple studies have demonstrated that surgery within 24–36 months of the onset of daily pain leads to higher rates of partial or complete pain relief, lower incidence of exocrine insufficiency, and reduced need for further interventions. Patients considered for TPIAT must have confirmed chronic pancreatitis or recurrent acute pancreatitis, significant lifestyle disruption, no reversible underlying cause, failure to improve with medical and endoscopic treatments, and preserved islet cell function. They should not have active cancer, substance abuse, significant heart, lung, or liver disease, poorly controlled psychiatric conditions, or an inability to support the recovery process.