: Myelofibrosis (MF) is characterized by anemia, splenomegaly, constitutional symptoms and bone marrow fibrosis. MF has no curative treatment to date, except for a small subset of patients that are eligible for allogeneic hematopoietic stem cell transplant. The discovery in recent years of the MF mutational landscape and the role of bone marrow microenvironment in disease pathogenesis has led to further insights into disease biology and consequentially rationally derived therapies.: We searched PubMed/Medline/American Society of Hematology (ASH) abstracts until November 2020 using the following terms: myelofibrosis, mouse models, pre-clinical studies and clinical trials. The development of targeted therapies is aimed to modify the history of the disease. Although JAK inhibitors showed encouraging results in terms of spleen and symptoms response, long term remissions and disease modifying ability is lacking. Beyond JAK inhibitors, a range of agents targeting proliferative, metabolic, apoptotic pathways, the microenvironment, epigenetic modification and immunomodulation are in various stages of investigations. We review pre-clinical data, preliminary clinical results of these agents, and finally offer insights on the management of MF patients.: MF patients refractory or with suboptimal response to JAK inhibitors, may be managed by addition of agents with differing mechanisms, such as bromodomain (BET), lysine demethylase 1 (LSD1), MDM2, or Bcl-Xl inhibitors which could prevent emergence of resistance. Immunotherapies as long-acting interferons, and calreticulin directed antibodies or peptide vaccination are eagerly awaited. Historically, therapeutic challenges in MF have arisen due to the fact that rationally derived therapies that are based on murine models have limited impact on fibrosis and underlying disease biology in human studies, the latter illustrates the complex multi-faceted disease pathogenesis of MF. Together, we not only suggest individualized therapy in MF that is guided by genomic signature but also its early implementation potentially in prefibrotic MF.