The groundbreaking discovery of the Janus-associated kinase 2 (JAK2) V617F mutation 10 years ago resulted in an unprecedented intensive basic and clinical research in Philadelphia-negative myeloproliferative neoplasms (MPNs). During these years, many new potential targets for therapy were identified that opened the era of targeted therapy for these diseases. However, only one new drug (ruxolitinib) has been approved during the past 40 years, and, although promising new therapies are evaluated, the armamentarium to treat MPN still relies on conventional drugs, like cytotoxic agents and anagrelide. The exact role of interferon (IFN) alfa still needs to be clarified in randomized studies, although it has been shown to be effective in MPNs for more than 25 years. The current therapeutic strategy for MPNs is based on the risk of vascular complication, which is the main cause of mortality and mortality in the medium term. However, the long-term outcome may be different, with an increasing risk of transformation to myelodysplastic syndrome or acute leukemia during follow-up times. Medicines able to change this natural history have not been clearly identified yet, and allogeneic stem cell transplantation currently remains the unique curative approach, which is only justified for patients with high-risk myelofibrosis or for patients with MPNs that have transformed to myelodysplasia or acute leukemia.