The Philadelphia-negative chronic myeloproliferative neoplasms (MPNs) are acquired stem cell neoplasms, in which a stem cell lesion induces an autonomous proliferative advantage. In addition to the JAK2V617 mutation several other mutations have been described. Recently chronic inflammation has been proposed as a trigger and driver of clonal evolution in MPNs. Herein, it is hypothesized that sustained inflammation may elicit the stem cell insult by inducing a state of chronic oxidative stress with elevated levels of reactive oxygen species (ROS) in the bone marrow, thereby creating a high-risk microenvironment for induction of mutations due to the persistent inflammation-induced oxidative damage to DNA in hematopoietic cells. Alterations in the epigenome induced by the chronic inflammatory drive may likely elicit a “epigenetic switch” promoting persistent inflammation. The perspectives of chronic inflammation as the driver of mutagenesis in MPNs are discussed, including early intervention with interferon-alpha2 and potent anti-inflammatory agents (e.g. JAK1-2 inhibitors, histone deacetylase inhibitors, DNA-hypomethylators and statins) to disrupt the self-perpetuating chronic inflammation state and accordingly eliminating a potential trigger of clonal evolution and disease progression with myelofibrotic and leukemic transformation.