Idiopathic hypereosinophilic syndrome is a largely heterogeneous disorder defined as persistent, marked hypereosinophilia of unknown origin complicated by end-organ damage. Recent research in cellular and molecular biology has led to the characterization of distinct underlying hematological disorders, primitively involving cells of the myeloid or lymphoid lineage. The ability to classify many hypereosinophilic syndrome patients on the basis of pathogenesis of hypereosinophilia has radically changed therapeutic perspectives. Indeed, imatinib mesylate has become first-line therapy for patients in whom the FIP1L1-PDGFRalpha fusion gene is detected, whereas corticosteroids remain the mainstay for management of patients in whom hypereosinophilia is secondary to the overproduction of interleukin 5 by abnormal T-cells. Use of monoclonal anti-interleukin-5 antibodies in the latter group of patients has a strong rationale and could decrease cumulative corticosteroid doses and toxicity. As far as prognosis of these disease variants is concerned, hypereosinophilic syndrome patients with the FIP1L1-PDGFRalpha fusion gene may develop acute myelogenous (eosinophilic) leukemia, whereas those with clonal interleukin-5-producing T-cells have an increased risk of developing T-cell lymphoma. It is currently unclear whether timely therapeutic intervention in such patients could interfere with long-term progression toward malignant hematological disorders.