AbstractHypereosinophilic syndrome (HES) is a rare disorder that is characterized by persistent and marked eosinophilia combined with organ system dysfunction. HES has substantial clinical heterogeneity but can be fatal without treatment, especially in patients who present with a myelodysplastic variant of the disorder. Although the pathophysiology of HES is poorly defined, dysregulation of cytokines (interleukin 5 [IL‐5], IL‐3, granulocyte‐macrophage colony‐stimulating factor [GM‐CSF]) responsible for the maturation of eosinophils is a primary feature. Of these cytokines, IL‐5 appears to have the greatest role in the regulation of eosinophil maturation. There is no Food and Drug Administration‐approved treatment for HES as yet; current strategies are designed to lower blood eosinophils and attempt to limit end‐organ damage. Historically, corticosteroids and cytotoxic agents have been the mainstays of therapy, with biological response modifiers such as interferon‐alpha also effective in some patients. However, despite improvements in survival, available agents have significant limitations in terms of efficacy, tolerability, and long‐term toxicity. More recently, new agents directed at specific targets in the pathogenesis of HES have been developed. These include imatinib mesylate, a tyrosine kinase inhibitor, and more recently, mepolizumab, an anti‐IL‐5 monoclonal antibody. In a small case series of patients, these agents have been shown to produce hematological and clinical responses in patients with HES, although they may be effective in different subsets of patients. These targeted therapies have the potential to improve clinical outcomes and to further the understanding the pathophysiology of this difficult‐to‐treat condition. Am. J. Hematol. 80:148–157, 2005. © 2005 Wiley‐Liss, Inc.