Systemic mastocytosis (SM) is a heterogeneous disease with 6 subtypes, including systemic mastocytosis with associated clonal hematologic nonmast cell lineage disease (SM-AHNMD). Bone marrow biopsy specimens show multifocal aggregates of mast cells with predominantly spindle-shaped morphology associated with a myeloid or, less frequently, a lymphoproliferative neoplasm defined by World Health Organization criteria. Neoplastic mast cells abnormally express CD2 and/or CD25, which may be detected by flow cytometry or immunohistochemistry. The pathogenesis of SM-AHNMD is not well understood; however, combined KIT tyrosine kinase receptor mutations and additional genetic events in myeloid stem cells may have a pathogenic role. Reactive mast cell hyperplasia, monocytic/histiocytic proliferations, SM without sufficient criteria for a diagnosis of AHNMD, atypical mast cells associated with PDGFRA rearrangements, and other tryptase-positive myeloid proliferations should be excluded. Overall, the prognosis is poor and largely related to the AHNMD. Cytoreductive therapies, splenectomy, allogeneic bone marrow transplant, and tyrosine kinase inhibitors, excluding imatinib, may have potential efficacy in the treatment of these diseases.