Exocrine pancreatic insufficiency (EPI) is associated with conditions including cystic fibrosis (CF), chronic pancreatitis (CP), and pancreatic surgery (PS). The symptoms include maldigestion, malnutrition, weight loss, flatulence, and steatorrhea. Pancreatic enzyme replacement therapy (PERT) is the standard treatment for EPI; it is regulated in many countries and most recently in the USA following a US FDA mandate for all PERT manufacturers to submit new drug applications. Pancrelipase delayed-release capsules (CREON®, Abbott, Marietta, GA, USA) have been available in Europe since 1984 and in the USA since 1987; a new formulation was the first PERT to gain approval in the USA in 2009. The efficacy and safety of CREON have been demonstrated in double-blind, randomized, placebo-controlled trials in patients with CF aged ≥7 years and in patients with CP or post-PS. The data consistently demonstrate significantly better fat and nitrogen absorption with CREON versus placebo, and improvements in clinical symptoms, stool frequency, and body weight. Additionally, efficacy and safety of CREON have been shown in open-label studies in young children with CF (aged 1 month to 6 years), with control of fat malabsorption and control of clinical symptoms. The most commonly reported adverse events (AEs) with PERT are gastrointestinal disorders and allergic skin reactions. In clinical studies, CREON was well tolerated with very few withdrawals due to AEs and a low frequency of AEs judged treatment related, regardless of patient age. To further support the known safety profile of PERT, all manufacturers are required to investigate risk factors for fibrosing colonopathy, a rare gastrointestinal complication of CF, and the theoretical risk of viral transmission from porcine-derived PERT products. Together, the clinical study data and wealth of clinical experience suggest that CREON is effective and safe in patients with EPI regardless of etiology, with a very favorable risk-benefit profile.