Myeloproliferative neoplasms (MPNs) include Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML) and the Ph- diseases primary myelofibrosis (PMF), polycythemia vera (PV) and essential thrombocythemia (ET). Since FDA approval of imatinib in 2001, CML treatment has been focused on tyrosine kinase inhibitors. With these targeted therapies, imatinib-resistant CML has emerged as a major problem. Second generation tyrosine kinase inhibitors (TKIs) have allowed for effective treatment of some patients with imatinib resistance, but bcr-abl mutants such as T315I remain problematic. Additional agents are in development and are discussed here. New clinical issues with TKI treatment include premature termination of therapy due to adverse-effects, the cost of therapy, and the apparently indefinite duration of treatment in patients who have achieved complete molecular response (CMR). In contrast to Ph+ CML, targeted therapy for Ph- MPNs is novel and of less clear therapeutic potential. New insights into Ph- MPNs include alterations in the JAK-STAT signaling pathway, particularly as mediated by the JAK2 V617F mutation. The recent development of multiple JAK2 inhibitors has provided hope for the rational and effective management of these disorders. Recently, ruxolitinib was approved as therapy for PMF. Current data suggests, however, that given its vital cell signaling function, the therapeutic benefit of targeting Jak kinases in general, or JAK2 specifically may be less than that derived from ABL-directed TKI treatment of CML. This review focuses on the current treatment options for CML and Philadelphia chromosome negative myeloproliferative neoplasms (MPNs) and limitations faced in current clinical practice.