**Abstract**

Malignant pleural mesothelioma (MPM) is a tumor with a relatively low incidence, but whose carcinogenesis, for the most part, involves epigenetic factors that keep its heterogeneity and sometimes are a therapeutic target or an obstacle to the effectiveness of the newest treatments. This chapter summarizes the principal epigenetic dysregulation mechanisms involved in the MPM pathogenesis. The most studied mechanism is hypermethylation mediated by DNA methyltransferases (DNMTs) in different tumor suppressor genes, and the relation with asbestos fiber exposure, which represents the main risk factor. Physiopathology is related to chronic inflammation mediated by free radicals that produce chromosomal alterations, genomic instability, increased angiogenesis, and tumor invasion factors like EGFR, FGFR, TGF-B, and PDGF. Additionally, independent methylation pathways that produce gene silencing such as polycomb complex and SWI/SNF mutation are reviewed. Finally, other mechanisms are described such as hypomethylation with imprint loss and prooncogenic gene activation that induce immunological responses, as well as acetylation, deacetylation, and demethylation in the chromatin and histone context.

**Keywords:** malignant pleural mesothelioma, epigenetics, hypermethylation, asbestos, genomic instability
