Resection of pancreas, in particular pancreaticoduodenectomy, is a complex procedure, commonly performed in appropriately selected patients with benign and malignant disease of the pancreas and periampullary region. Despite significant improvements in the safety and efficacy of pancreatic surgery, pancreaticoenteric anastomosis continues to be the “Achilles heel” of pancreaticoduodenectomy, due to its association with a measurable risk of leakage or failure of healing, leading to pancreatic fistula. The morbidity rate after pancreaticoduodenectomy remains high in the range of 30% to 65%, although the mortality has significantly dropped to below 5%. Most of these complications are related to pancreatic fistula, with serious complications of intra-abdominal abscess, postoperative bleeding, and multiorgan failure. Several pharmacological and technical interventions have been suggested to decrease the pancreatic fistula rate, but the results have been controversial. This paper considers definition and classification of pancreatic fistula, risk factors, and preventive approach and offers management strategy when they do occur.