Myelofibrosis (MF) is a hematopoietic stem cell malignancy classified as a myeloproliferative neoplasm (MPN). The clinical course of individuals with MF is heterogeneous and characterized by constitutional symptoms, bone marrow myeloproliferation and fibrosis, progressive cytopenias, and symptomatic splenomegaly. Historically, patients with this debilitating disease have had limited treatment options, and disease-modifying agents were not available. Hematopoietic stem cell transplantation is the only potentially curative therapy, but it is only an option for select patients. The discovery of an activating point mutation in the Janus kinase 2 gene (JAK2V617F) in a significant portion of patients with MPNs led to improved understanding of the pathobiology of these disorders and prompted rapid development of JAK inhibitors. Ruxolitinib (Jakafi) is the first-in-class and only JAK inhibitor currently approved by the US Food and Drug Administration (FDA) for the treatment of patients with MF; approval was based on the results of the COMFORT (COntrolled MyeloFibrosis study with ORal JAK inhibitor Treatment) I and II studies. While not a curative option, ruxolitinib offers great palliative potential and results in significant reduction in splenomegaly and improvement in constitutional symptoms in the majority of treated patients, thus improving their quality of life and performance status. Additionally, ruxolitinib is the only agent that has demonstrated a survival benefit in patients with MF. The optimal use of ruxolitinib for MF patients is challenging and complex. In this article, we provide updated data on ruxolitinib therapy for patients with MF and offer expert opinion on the appropriate use of this agent in the community practice.