The relationship between asbestos exposure and malignant mesothelioma is established since the middle of the twentieth century. From this time, scientific researches have progressed investigating the mechanism of action of asbestos on mesothelial cells, and more intensively during the beginning of the twenty-first century the analysis of the molecular changes in mesothelioma. Indeed, asbestos fibers were reported to induce chromosomal and genetic damage in mammalian cells. Mesothelioma is characterized by chromosomal alterations, which include numerous chromosome rearrangements, gene mutations, and gene deletions. Recent studies have enhanced our knowledge of the molecular landscape of mesothelioma, emphasizing mutations targeting more specifically tumor suppressor genes, differential gene expression, and DNA methylation in comparison with normal cells and between mesotheliomas, expression of noncoding RNAs, and alterations of regulatory pathways. Researches also provided knowledge of susceptibility factors in malignant mesothelioma families and relationships with asbestos exposure. It is time to review the recent advances in asbestos-induced molecular changes related to mesothelial carcinogenesis.