Effective treatment of malabsorption due to severe pancreatic exocrine insufficiency requires delivery of sufficient enzymatic activity into the duodenal lumen simultaneously with meal nutrients. To achieve this, modern therapeutic concepts recommend administration of 25,000 to 40,000 units of lipase per meal using pH-sensitive pancreatin microspheres. In case of treatment failure, dosage should be increased two to three times. If this still is not successful, compliance may be checked by measurement of fecal chymotrypsin, although this is not a standardized procedure. In the compliant patient, diagnosis of pancreatic exocrine insufficiency needs to be reviewed, particularly cases of celiac disease, (concomitant) bacterial overgrowth, and blind loop syndrome, as well as giardiasis, which need to be excluded or otherwise be treated specifically. Finally, additional acid suppression with application of unprotected pancreatin and/or reduced fat intake may help to control malabsorption. Still, in most patients, lipid digestion cannot be completely normalized by current standard therapy. On the one hand, this leads to loss of energy that may only partly be compensated for by increased nutrient intake. On the other hand, increased nutrient exposition of distal intestinal sites may release excessive amounts of mostly inhibitory distal intestinal neurohumoral mediators, and thereby disturb gastrointestinal secretory and motor functions. Consequently, future developments are needed for optimizing treatment.