Malignant mesothelioma is an aggressive cancer refractory to current therapies, the incidence of which is expected to rise in the next decades. Exposure to asbestos is a well known risk factor, as InternationalAgency for Research and Cancer (IARC) classified this compound as group I (carcinogenic to humans). The lack of tumor biomarkers for diagnosis and medical survey plays a fundamental role for the development of a universally accepted therapeutic approach. In this review we evaluated the mechanism of asbestos carcinogenesis by analyzing activated oncogenes, genetic predisposition, and SV40 infection as cofactors. Therefore, interest has focused on microRNAs, 19-25 nucleotide-long single-stranded RNAs that negatively regulate gene expression by modulating translational efficiency of target genes involved in numerous cellular processes including development, differentiation, proliferation, apoptosis, and stress response. The analysis revealed a differential expression of miRNAs between mesothelioma and mesothelial cells, suggesting their potential role as oncogenes or tumor suppressor genes in mesothelioma oncogenesis. We have also investigated the role of polymorphism in the etiology and pathogenesis of mesothelioma, in order to evaluate the association between disease linked to asbestos exposure andgenetic variability. The identification of dysregulated miRNAs or frequent genetic polymorphisms as potential diagnostic biomarkers or as prognostic factors for malignant mesothelioma could facilitate the surveillance procedure of subjects exposed to asbestos.