Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder characterized by overlapping features of myelodysplastic syndromes and myeloproliferative neoplasms. Diagnosis is based on the presence of persistent (>3 months) peripheral blood monocytosis (>1 × 109/L), along with bone marrow dysplasia. Clonal cytogenetic abnormalities occur in ˜20–30% of patients, while >90% have gene mutations. Mutations involving TET2 (˜60%), SRSF2 (˜50%), ASXL1 (˜40%), and RAS (˜30%) are frequent; with only ASXL1 mutations negatively impacting overall survival. Two molecularly integrated, CMML-specific prognostic models include; the Groupe Français des Myélodysplasies (GFM) and the Molecular Mayo Model (MMM). The GFM model segregates patients into 3 groups based on: age >65 years, WBC >15 × 109/L, anemia, platelets <100 × 109/L, and ASXL1 mutation status, with respective median survivals of 56 (low), 27.4 (intermediate), and 9.2 (high) months. The MMM is based on ASXL1 mutational status, absolute monocyte count >10 × 109/L, hemoglobin <10 g/dL, platelets <100 × 109/L and circulating immature myeloid cells. This model stratifies patients into four groups; high (≥3 risk factors), intermediate-2 (2 risk factors), intermediate-1 (1 risk factor) and low (no risk factors), with median survivals of 16, 31, 59, and 97 months, respectively. Hypomethylating agents such as 5-azacitidine and decitabine are commonly used, with overall response rates of ˜30–40% and complete remission rates of ˜7–17%. Allogeneic stem cell transplant is the only potentially curative option, but is associated with significant morbidity and mortality. Individualized therapy, including epigenetic modifiers and small molecule inhibitors, are exciting prospects. Am. J. Hematol. 91:632–642, 2016. © 2016 Wiley Periodicals, Inc.