BCR-ABL-negative myeloproliferative neoplasms include primary myelofibrosis, polycythemia vera, and essential thrombocythemia. Clonal stem cell proliferation and dysregulated JAK/STAT molecular pathways characterize these hematologic malignancies. Symptoms experienced by patients are heterogeneous including excessive and disabling fatigue, early satiety, anorexia, pruritus, bone pain, night sweats, cachexia, abdominal pain and discomfort, and cognitive complaints. Patients also experience impaired quality of life along with decreased overall survival. New targeted drug therapies, including JAK2 inhibitors, have demonstrated remarkable success in alleviating the myeloproliferative neoplasm (MPN) symptomatic burden, reducing splenomegaly and improving quality of life while offering overall survival benefit. Within the USA, FDA approval has only been granted to use JAK2 inhibitors in intermediate- to high-risk myelofibrosis. However, given that low-prognostic-scoring patients have been shown to have considerable symptomology, there is a possibility that lower-risk patients may benefit from therapy. More than ever, the need for accurate MPN symptom burden assessment and subsequent addition of targeted therapies is critical in the treatment of MPNs. This article discusses the role of MPN symptom burden and quality of life as therapeutic targets in the context of recent MPN clinical advances.