The current standard‐of‐care for treatment of myelofibrosis (MF) comprises inhibitors of the Janus kinase (JAK)/signal transducers and activators (STAT) pathway; however, despite their ability to alleviate symptoms, they do not appear to modify underlying disease and have not demonstrated substantial survival benefit. Allogeneic‐hematopoietic stem cell transplantation remains the only curative option for patients with MF but is limited to a subset of high‐risk and fit patients. Early disease modification could positively affect disease trajectory for lower risk patients with MF as well as those with conditions that can precede MF, such as polycythemia vera and essential thrombocythemia. Here, the authors discuss critical unmet needs in the MF treatment paradigm, including: the need for safe, impactful therapies for lower risk patients, thus allowing intervention when success is most likely; better development of first‐line therapies (likely highly novel or combination strategies) for intermediate‐risk/higher risk patients; and approved drugs to manage cytopenia. Finally, a consensus definition of disease modification is needed that informs trial design, allowing the development of clinical end points that enable understanding of therapies and responses and that facilitate the development of therapies that work according to this definition. Through close collaboration between clinicians, patients, and the pharmaceutical industry, better efforts to define benefit and identify patients most likely to benefit from a particular combination or treatment strategy should enable the development of more effective and safe treatments to extend and improve quality of life for patients with MF. Early disease modification could positively affect the disease trajectory for patients with myelofibrosis. Herein, the authors discuss critical unmet needs in the myelofibrosis treatment paradigm, including safe therapies for lower risk patients, better development of first‐line therapies for intermediate‐risk/higher risk patients, approved drugs to manage cytopenia, and a consensus definition of disease modification.