Systemic mast cell disease/mastocytosis (SMCD) is best defined as a multitopic proliferation of cytologically and/or functionally abnormal tissue mast cells (TMC). SMCD preferentially involves the bone marrow, skin, spleen, liver, and lymph nodes. The histopathological diagnosis of SMCD may be very difficult to make, and the disease is often not considered in the differential diagnosis of lymphoreticular neoplasia. In suspected cases of SMCD, basic dyes such as Giemsa and toluidine blue are useful to demonstrate the specific metachromatic granules of TMC. The naphthol AS-D chloroacetate esterase reaction has also proved to be very reliable for enzyme-histochemical identification of TMC. Major diagnostic problems may arise in cases of malignant or "aggressive" SMCD exhibiting tissue infiltrates consisting predominantly of highly atypical, non-metachromatic TMC, which are usually also only weakly reactive for chloroacetate esterase. Immunostaining with antibodies against the mast cell-specific proteases tryptase and chymase has proved to be of great value of establishing the correct diagnosis in such cases. Anti-tryptase antibodies have major diagnostic significance due to their extremely high sensitivity and specificity. The classification of SMCD is controversial, but there is increasing support for the differentiation of at least two major subtypes that differ in prognosis: (i) a benign or "indolent" variant in which skin involvement (urticaria pigmentosa-like skin lesions) is usual, but associated malignant hematological disorders are rare; and (ii) a malignant or "aggressive" variant where skin involvement is usually absent but concomitant malignant hematological disorders (myelodysplastic and myeloproliferative syndromes and acute non-lymphocytic leukemias) are very common. Preliminary molecular biological studies of a few cases of malignant SMCD using the recently developed HUMARA assay have yielded evidence that the disease is monoclonal.