The molecular profiling of myeloproliferative neoplasms (MPNs) has introduced a paradigm shift in the process of diagnosis, prognostication, monitoring and treatment of these diseases. The discovery of the BCR-ABL fusion oncogene is an example of a remarkable bench-to-bedside story. It has provided a comprehensive explanation of the pathogenesis of chronic myelogenous leukemia, and has resulted in the development of excellent treatment strategies. It has led to the use of advanced diagnostic techniques, such as fluorescence in situ hybridization and PCRs that allow for more effective means to monitor disease treatment, including the detection of minimal residual disease, early relapse and drug resistance. Unlike chronic myelogenous leukemia, the exact molecular pathways for the BCR-ABL-negative MPNs have not been completely elucidated. The discoveries of the JAK2 and the MPL mutations have set the ball rolling in trying to achieve this target. The JAK2 mutational screen has provided us with a relatively simple screening assay to establish clonality in the setting of MPNs. In patients with clonal eosinophilic disorders and mast cell disease, the use of molecular diagnostics to identify novel mutations and gene rearrangements, has resulted in superior diagnostic and therapeutic strategies.