Myeloproliferative neoplasms (MPNs) are associated with the fewest number of mutations among known cancers. The mutations propelling these malignancies are phenotypic drivers providing an important implement for diagnosis, treatment response monitoring, and gaining insight into the disease biology. The phenotypic drivers of Philadelphia chromosome negative MPN include mutations in JAK2, CALR, and MPL. The most prevalent driver mutation JAK2V617F can cause disease entities such as essential thrombocythemia (ET) and polycythemia vera (PV). The divergent development is considered to be influenced by the acquisition order of the phenotypic driver mutation relative to other MPN-related mutations such as TET2 and DNMT3A. Advances in molecular biology revealed emergence of clonal hematopoiesis (CH) to be inevitable with aging and associated with risk factors beyond the development of blood cancers. In addition to its well-established role in thrombosis, the JAK2V617F mutation is particularly connected to the risk of developing cardiovascular disease (CVD), a pertinent issue, as deep molecular screening has revealed the prevalence of the mutation to be much higher in the background population than previously anticipated. Recent findings suggest a profound under-diagnosis of MPNs, and considering the impact of CVD on society, this calls for early detection of phenotypic driver mutations and clinical intervention.