The diagnostic value of JAK2 mutational analysis in myeloproliferative neoplasms (MPN) is now well established and endorsed by the World Health Organization classification system for hematologic malignancies. The current review is focused on the prognostic impact and therapeutic relevance of JAK2 and other MPN-associated mutations in polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Mutations involving JAK2, MPL, TET2, and ASXL1 are discussed. In general, within a specific disease category, the mere presence or absence of any one of these mutations does not appear to correlate with survival or development of blast phase disease, myelofibrosis, or thrombosis. In contrast, interesting associations between JAK2V617F allele burden and clinical outcome (e.g. lower quartile range allele burden and shorter survival in PMF and higher allele burden and fibrotic transformation in PV) have been made, but require further validation, and their impact on treatment choices is not clear. Similarly, although detection of JAK2V617F status post allogeneic hematopoietic cell transplant indicates minimal residual disease, the general use of mutant allele burden for monitoring treatment response has not been systematically studied. Current information on mutational status and response to JAK2 inhibitor drug therapy is too preliminary to draw any conclusions.