Genetic and hereditary etiologies of pancreatitis, which are more common in pediatric patients, impact disease progression, response to conventional surgical approaches, and risk of future malignancy. Thus, consideration of genetic risk may play an important role in determining eligibility for and timing of total pancreatectomy with islet autotransplantation (TPIAT), particularly in children. Multiple genes have been implicated as risk factors for development of acute recurrent and chronic pancreatitis (ARP and CP), including PRSS1, CFTR, SPINK1, and others. Genetic variants may predispose to pancreatitis independently or increase risk of development of pancreatitis in the setting of additional risk factors, such as smoking or the presence of an anatomic variant. Genetic analysis in adults and children with idiopathic ARP or CP can serve a prognostic role, as pancreatitis-associated gene variants are associated with higher risk of recurrent pancreatitis after an initial episode, earlier onset of CP, and often a more severe disease course. Additionally, the presence of a pancreatitis-associated gene variant is associated with decreased efficacy of conventional, pancreas-sparing surgeries, which may delay ultimate TPIAT. Islet yield is an important predictor of insulin independence after TPIAT. Younger age and shorter duration of disease at the time of surgery are associated with higher islet yield, and prior surgical interventions are associated with lower islet yield during TPIAT. Given the evidence that alternate surgical approaches for CP are less successful in alleviating symptom burden in patients with hereditary and genetic pancreatitis and may lead to reduced islet yield at the time of TPIAT, pancreas-sparing surgery should be approached with caution in this population.