Total pancreatectomy with islet autotransplantation (TPIAT) is a complex surgical procedure aimed at alleviating symptoms in patients with chronic and acute recurrent pancreatitis while minimizing postoperative diabetic complications. This surgery presents significant challenges, particularly during pancreatectomy. The inherent operative risks arise from the retroperitoneal location of the gland and its proximity to vital structures; the inflammatory etiology of the disease process, resulting in destruction of normal anatomic planes; and prior pancreatic interventions, leading to a significant burden of adhesions, difficult dissection, and increased risk of intraoperative complications. Meticulous reconstruction techniques with a focus on well-vascularized anastomoses are critical to avoid postoperative complications. The choice of intestinal reconstruction, e.g., Roux-en-Y, modified Billroth II, or pylorus preservation, may affect the specifics of the postoperative challenges. Irrespective of islet infusion technique, large tissue volume and portal pressure greater than 25 cm H2O are associated with risks of portal vein thrombosis and bleeding. Careful hemostasis of the operative field, monitoring of intraportal pressures, and heparinization during islet infusion are critical to avoid these complications. Postoperative bleeding, infection, and small-bowel obstruction are the most common causes for reoperation following TPIAT; gastrointestinal and infectious complications are the most frequent reasons for early readmissions. A minimally invasive approach to TPIAT is feasible with comparable surgical outcomes, but complications during port placement, effects of CO2 pneumoperitoneum on the cardiovascular and respiratory systems, and injuries associated with introduction and manipulation of surgical instruments should be considered. Comprehensive preoperative evaluation, technical expertise, careful patient selection, and effective postoperative care are essential to mitigate risks and improve overall outcomes in this complex surgical procedure.