During the past two decades the immunophenotype of normal, reactive, and neoplastic mast cells (MCs) has been established. These studies have convincingly demonstrated that MCs form a separate lineage within the myeloid cell family. A most intriguing finding was that in contrast to normal MCs, neoplastic MCs in systemic mastocytosis (SM) aberrantly express several lymphoid marker antigens such as CD2 and CD25. This phenomenon has now been topped by the unexpected observation that neoplastic MCs in aggressive variants of SM and MC leukemia (leukemic variant of SM) aberrantly express CD30, whereas this antigen, Ki-1, is not detectable or is expressed only weakly in MCs in most patients with indolent SM. These observations may have implications for the evolution of SM as well as for diagnostic evaluation and grading in these patients. Moreover, these observations suggest that advanced SM has to be considered as a differential diagnosis of CD30-positive lymphoid neoplasms. Finally, CD30 may be considered as a potential target of antibody-based therapeutic intervention in advanced mast cell disorders.