An increase in mast cell (MC) numbers in hemopoietic tissues may be associated with (a) primary neoplastic MC disease (mastocytosis); (b) non-mast cell lineage myelogenous disorders (myelodysplastic or myeloproliferative syndromes and myeloid leukemias); or (c) reactive, i.e. non-clonal states (MC hyperplasia and reactive mastocytosis). However, the histologic discrimination between hyperplastic states and neoplastic MC proliferative disorders is sometimes very difficult. MC hyperplasia is characterized by a diffuse increase in mature, round or spindle-shaped, metachromatic MC that are loosely scattered throughout the tissue and do not form dense focal infiltrates, even in states of marked hyperplasia. However, loosely scattered MC are also a prominent feature of many cases of myelodysplastic syndromes and acute leukemia involving the MC lineage. In contrast, the demonstration of dense, focal and/or diffuse MC infiltrates can be regarded as indicative of primary MC disease/mastocytosis. In addition to the highly diagnostic focal MC infiltrates, mastocytosis may also present with a predominantly diffuse or a mixed (diffuse and focal) infiltration pattern. The relatively rare diffuse pattern is usually dominated by atypical, often hypogranulated or even non-metachromatic MC and is associated with the aggressive or frankly malignant subtypes of systemic mastocytosis and MC leukemia. Although the demonstration of MC infiltrates in Giemsa-stained tissue sections is still very important for the diagnosis of mastocytosis, immunohistochemical techniques using antibodies against MC-associated antigens such as tryptase or c-kit (CD117) are essential for the identification of highly atypical, hypogranulated MC, especially in MC leukemia, and for the detection of small and even minute MC infiltrates.