Systemic mastocytosis (SM), as opposed to cutaneous-only mastocytosis, implies the presence of neoplastic mast cell infiltration in extracutaneous tissue. Mast cell disease in adults is often systemic and often involves the bone marrow. Typical clinical and laboratory features of SM include urticaria pigmentosa, mast cell mediator symptoms (eg, headache, flushing, lightheadedness, urticaria and pruritus, nausea, diarrhea, abdominal pain, and vasodilatory shock), bone pain (eg, osteoporosis, lytic bone lesions, and fractures), hepatosplenomegaly, cytopenia, eosinophilia, elevated serum tryptase and histamine, and bone marrow fibrosis and angiogenesis. SM may be indolent (no evidence of organ dysfunction), aggressive (presence of organ dysfunction), associated with another often chronic myeloid hematologic disease (SM-AHD), or present as mast cell leukemia or sarcoma. Mast cell-mediator symptoms are treated with histamine antagonists and cromolyn sodium. Indolent SM does not require cytoreductive therapy. Aggressive SM and SM-AHD are managed based on their molecular profile. Recent information suggests that FIP1-like-1-platelet-derived growth factor receptor-alpha(+) SM responds well to imatinib mesylate, whereas interferon-alpha should be considered as a first-line treatment in all of the other cases, including patients with Asp816Val(+) SM. Cladribine has been shown to be effective in patients who develop resistance to interferon treatment.