With the exception of chronic myeloid leukemia (CML), chronic myeloproliferative disorders (CMPDs) are a heterogeneous spectrum of conditions for which the molecular pathogenesis is not well understood. Most cases have a normal or aneuploid karyotype, but a minority present with a reciprocal translocation that disrupts specific tyrosine kinase genes, most commonly PDGFRB or FGFR1. These translocations result in the production of constitutively active tyrosine kinase fusion proteins that deregulate hemopoiesis in a manner analogous to BCR-ABL. With the advent of targeted signal transduction therapy, an accurate clinical and molecular diagnosis of CMPDs has become increasingly important. Currently, patients with PDGFRB or ABL fusion genes are candidates for treatment with Imatinib (STI571), but it is likely that alternative strategies will be necessary for the treatment of most other patients.