Recent insights into the pathophysiology of chronic myelomonocytic leukemia (CMML) have been obtained by the molecular and biological characterization of primary leukemic cells from patients and from animal models. Almost 3 decades ago extensive myeloid colony growth in semisolid cultures without exogenous growth factors was observed as an in vitro characteristic of a subgroup of CMML patients. Recent data suggest that this phenomenon was probably the first indication of an hyperactive RAS signaling pathway in these patients. Although the mutation landscape in CMML is heterogeneous and molecular aberrations in other signaling components can be found in some patients, the RAS pathway seems to play the major pathophysiological role in the majority of CMML patients with myeloproliferation (MP), disease progression and transformation into secondary acute myeloid leukemia (AML). There is also increasing evidence indicating that the MP-CMML is a RAS pathway driven disease which is superimposed onto age-related clonal hematopoiesis.