In approximately one-third of cases, patients with mastocytosis can display various disabling general and neuropsychological symptoms. General signs may have a major impact on quality of life. Neurologic symptoms are less frequent. In a majority of cases, the pathophysiology of these symptoms is not known but could be linked to tissular mast cell infiltration, mast cell mediator release, or both. Treatments aiming at reducing mast cell number and/or stabilizating mast cells may be useful. Preliminary results suggest that treatment with kinase inhibitors may improve symptoms of depression and cognitive impairment.