Clinical conditions in which secondary maldigestion associated with exocrine pancreatic insufficiency occur include chronic pancreatitis, cystic fibrosis, pancreatic cancer, partial or total gastrectomy, and pancreatic resection. Maldigestion can cause serious weight loss, nutritional deficiencies, and subjective complaints associated with steatorrhea. The various causes of exocrine pancreatic insufficiency may be associated with cause-related changes in gastrointestinal physiology, such as changes in gastrointestinal intraluminal pH, bile acid metabolism, gastric emptying, and intestinal motility. Therefore, to optimize the efficacy of treatment, the management of exocrine pancreatic insufficiency must be individually tailored to account for both the underlying cause and any associated disturbance in gastrointestinal physiology. In addition, the properties of the pancreatic enzyme preparations and adjuvant drugs need to be taken into consideration. This paper reviews the pathophysiological mechanisms of maldigestion in exocrine pancreatic insufficiency, discusses the efficacy of different therapy regimens, and gives guidelines for a cause-related and patient-tailored treatment with respect to both drug therapy and dietary counselling.