Pancreatic exocrine insufficiency (PEI) is one of the well known causes of malabsorption syndrome. An insufficient secretion of pancreatic enzymes and bicarbonate secondary to different pancreatic diseases and upper gastrointestinal and pancreatic surgery leads to maldigestion and malabsorption of nutrients. Patients with PEI may present with symptoms of malabsorption and different nutritional deficiencies. Recent data support the high clinical relevance of PEI and its treatment. Deficiencies of fat-soluble vitamins, proteins, micronutrients and antioxidants in patients with PEI are associated not only with an increased risk of osteoporosis and sarcopenia but also of cardiovascular events and mortality. Pancreatic enzyme replacement therapy (PERT) allows improving fat and protein digestion, relieving maldigestion-related symptoms, normalizing the nutritional status, and improving quality of life of patients with PEI. Recent data support the efficacy of PERT on survival in patients with pancreatic cancer. Dose of oral pancreatic enzymes should be adequate to normalize the nutritional status of PEI patients. Increasing evidence supports the relevance of PEI management by dietary advice and appropriate PERT. Well designed and powered randomized, placebo-controlled clinical trials are needed to further evaluate the clinical impact of PEI and its treatment in clinical practice.