The term mastocytosis covers a heterogeneous group of disorders characterized by the abnormal growth and accumulation of MCs in one or more organ systems. Clinical symptoms occur from the release of chemical mediators or pathologic infiltration of MCs. CM typically presents as UP and is a benign disease confined to the skin. In many cases, particularly in children, this disease regresses spontaneously. By contrast, SM is a clonal persistent disease of MC-committed or precommitted hematopoietic progenitors. In most of these patients, the transforming c-kit mutation Asp-816-Val is detectable. The clinical course in SM is variable. Many cases remain in an indolent stage over decades. In a few patients, significant organopathy is found, and this may lead to the diagnosis of aggressive SM. In other patients, AHNMD is diagnosed. MCL is a rare form of SM characterized by leukemic spread of MCs in the marrow and blood and rapid progression. In contrast to indolent SM, patients with MCL or aggressive SM often present without UP-like skin lesions. Patients with indolent SM should be treated with mediator-targeting drugs but not with cytoreductive drugs. By contrast, patients with aggressive SM or MCL are candidates for cytoreductive therapy. Some patients with aggressive SM may benefit from IFNalpha2b. Patients with rapid progression or MCL are candidates for more aggressive treatment, including cladribine, chemotherapy, and stem cell transplantation. In patients with SM-AHNMD, the SM should be treated as if no AHNMD is present, and the AHNMD should be treated as if no SM had been diagnosed.