Mastocytosis is characterized by an abnormal proliferation and accumulation of mast cells (MC) in one or more organ systems. The current WHO classification discriminates cutaneous mastocytosis (CM) and various forms of systemic mastocytosis (SM). While CM usually follows a bening and often self-limiting course, SM is a persistent disease in which a somatic KIT mutation at codon 816 (i.e. D816V) is detectable in MC in at least 80% of cases. Symptoms in mastocytosis result from MC-derived mediators and, less frequently, from destructive tissue infiltration by MC. The clinical course of SM is usually indolent, but sometimes it may be highly aggressive and rapidly devastating. KIT is a transmembrane class III receptor tyrosine kinase which is required for MC growth, differentiation, and functional activation. Mutations in codon 816 of the KIT gene result in ligand-independent (constitutive) activation of KIT signaling and, thus, may play a central role in the pathogenesis of SM. Since there are no curative options, therapy for the aggressive forms of SM is based on cytoreductive agents, e.g. interferon-alpha (IFN-alpha) and cladribine. The expression of KIT in neoplastic MC has led to the development of targeted therapies using tyrosine kinase inhibitors (TKI) like STI571 (Imatinib, Gleevec). Unfortunately, the KIT mutation D816V is associated with relative resistance against STI571. However, TKIs with activity against KIT D816V-positive cells have recently been developed, and some of them (dasatinib, nilotinib/AMN107, PKC412) are already tested in phase I/II trials. In addition, non-TK KIT signaling inhibitors (e.g. geldanamycin, rapamycin) or monoclonal antibodies directed against neoplastic MC may evolve as future therapeutic options.