Chronic pancreatitis in affected children is often progressive, resulting in debilitating pain, opioid use, recurrent hospitalization, missed school, and poor quality of life (QoL). The etiology in children is primarily genetic due to PRSS1, SPINK1, and CFTR mutations. A number of surgical procedures (partial resection/drainage) have been used, but due to diffuse gland involvement, pain recurs in >50% of patients. Total pancreatectomy with islet autotransplantation (TPIAT) is now increasingly being used to treat children with chronic pancreatitis refractory to medical and endoscopic treatment. TP is the only procedure that removes the root cause of the pain and theoretically eliminates the risk of pancreatic cancer. The islets of Langerhans are infused back into the patient’s liver, where they engraft in the sinusoids of the liver and produce insulin and prevent brittle diabetes. TPIAT surgery, even in very young children, is safe, with a low operative mortality (0–1%). Surgical complications occur in 20% of patients and include intra-abdominal bleeding (5.3%), bowel obstruction (5.3%), abdominal abscess (4%), enteric leak (2.6%), biliary leak (1.3%), and wound infection (1.3%). Pancreatitis-type pain and the severity of pain significantly improve in >90% of patients following TPIAT, and at 10 year follow-up, opioid use is <20%. Approximately 50% of children achieve insulin independence long term, and 90.3% of these patients do so within 1 year. Younger children (<12 years) are more likely to achieve insulin independence than older children (12–18) (56.0% versus 40.5%; p = 0.05). Quality of life improves dramatically after TPIAT, with most children reporting improved ability to participate in school and play activities with reduced days of missed school.