The myeloproliferative neoplasms (MPNs) are a particularly useful model for studying mutation accumulation in neoplastic cells, and the mechanisms underlying their acquisition. This review summarizes our current understanding of the molecular defects present in patients with an MPN, and the effects of mutations targeting Janus kinase 2 (JAK2)-mediated intracellular signaling on DNA damage and on the elimination of mutation-bearing cells by programmed cell death. Moreover, we discuss findings that suggest that the acquisition of disease-initiating mutations in hematopoietic stem cells of some MPN patients may be the consequence of an inherent genomic instability that was not previously appreciated. Am. J. Hematol. 2012. © 2012 Wiley Periodicals, Inc.