Myelofibrosis (MF) is a myeloproliferative neoplasm that is pathologically characterized by bone marrow myeloproliferation, reticulin and collagen fibrosis, and extramedullary hematopoiesis. Constitutive activation of the Janus associated kinase (JAK)-signal transducers and activators of transcription signaling pathway with resultant elevation in pro-inflammatory cytokine levels is the pathogenic hallmark of MF. JAK inhibitors, namely ruxolitinib, have been successful in alleviating symptoms and reducing splenomegaly, but therapy-related myelosuppression has led to the further development of highly selective JAK2 inhibitors. Additionally, ruxolitinib does not appear to affect the malignant hematopoietic clone substantially, evidenced by lack of molecular remissions, bone marrow histopathologic responses, and a proportion of treated patients developing progressive disease and leukemic transformation while receiving therapy. A number of other pharmacotherapeutic strategies are currently being explored in the clinic. Non-JAK inhibitor strategies being evaluated in MF include non-JAK signaling pathway inhibitors, epigenetic-directed therapies, immune-modulating agents, anti-fibrotic agents, and telomerase inhibitors. This review highlights the current landscape of MF pharmacotherapy and explores therapeutic advances underway.