The myeloproliferative neoplasms (MPNs) encompass a heterogenous set of diseases that have variable survival, but in the setting of treatment refractory and progressive disease, prognosis has been characteristically poor. JAK inhibition with ruxolitinib or fedratinib therapy has become the first line treatment for symptomatic or intermediate to high risk myelofibrosis. However, after three years of ruxolitinib therapy, approximately half of all patients with myelofibrosis will likely have stopped treatment. JAK inhibition failure represents a mixture of etiologies, including drug intolerance, suboptimal dosing, drug resistance, or progression of disease. JAK inhibition failure and accelerated/blast phase have now become the primary clinical challenges in the treatment of myelofibrosis and high risk polycythemia vera, and no phase III trials or clear treatment guidelines exist to guide management strategies in this setting. On the other hand, this represents an exciting time in treatment of JAK inhibitor failure and accelerated phase MPNs due to the advent of recently approved drugs as well as new targeted agents currently under investigation. In this article, we review the management options for these challenging clinical scenarios. We discuss the options for JAK inhibitor dose optimization and overcoming resistance by utilizing combinations of JAK inhibition, primarily ruxolitinib, with alternative commercially available therapies. For patients who have progressed, we discuss recent data regarding targeted therapy options approved for AML that represent potentially efficacious options in the progressive MPN setting. We also discuss the new clinical agents under development in MF and accelerated MPNs that may offer new therapeutic options in the years to come.