The term hypereosinophilic syndrome (HES) was initially introduced to describe a group of diseases all characterized by persistent unexplained hypereosinophilia. Additional names have subsequently been introduced to describe specific variants of HES, such as the myeloid variant and the lymphoid variant, or to indicate idiopathic HES, for which the cause of the eosinophilia is completely unknown. Molecular analysis led to the identification of the clonal origin of several subgroups of HES, clearly establishing these diseases as true leukemias. These cases of hypereosinophilia are now referred to as 'myeloid neoplasms associated with eosinophilia and abnormalities of PDGF receptor A and B (PDGFRA and PDGFRB), or FGF receptor 1 (FGFR1)'. In cases for which clonality is clear, but no PDGFRA, PDGFRB or FGFR1 rearrangement could be demonstrated, the term 'chronic eosinophilic leukemia, not otherwise specified' is preferred. Most importantly, patients with rearrangements of PDGFRA or PDGFRB can be efficiently treated with the kinase inhibitor imatinib. Additional potent kinase inhibitors have been identified, also including inhibitors that target FGFR1 and imatinib-resistant variants of PDGFRalpha. For treatment of unexplained hypereosinophilia and 'chronic eosinophilic leukemia, not otherwise specified; different therapeutic strategies are currently under investigation and promising results have been obtained using humanized anti-IL-5 antibodies. Further molecular understanding of the cause of these 'idiopathic' diseases may lead to the development of novel targeted therapies.