Systemic mastocytosis comprises disorders characterized by an accumulation of genetically altered mast cells in all organs and tissues due to an increased proliferation rate and reduced apoptosis of those pathologic mast cells. Release of their mediators can effectively influence organ function and can lead to systemic effects without inducing traces in routinely used laboratory parameters or imaging methods. In most cases, little invasive investigations allow diagnosing the disease and, hence, an appropriate therapy consisting of a basic medication with antihistamine and mast cell membrane-stabilizing compounds that should be supplemented, if required, by a medication adapted to individual symptoms, can be initiated. Because of the probably high prevalence of the disorder, systemic mastocytosis should be considered as a differential diagnosis in particular in the case of chronic gastrointestinal complaints such as abdominal pain/discomfort possibly associated with diarrhea, at an early stage.