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Diffuse mesothelioma is an invasive cancer that originates from the cells in the smooth tissue lining (serosal membrane) that surrounds various body cavities. While most cases originate in the pleural lining of the thoracic cavity, a subset primarily involves the peritoneum or, rarely, the pericardium or the tunica vaginalis. Advances in molecular biology have established that cancer heterogeneity is common across a wide variety of histogenetically diverse neoplasms and that 'mesothelioma' as a disease is the same. It is increasingly evident that age, sex, and anatomic site-specific variations do exist which are often driven by recognized and recurrent mutations although a high degree of inter- and intra-tumor heterogeneity is present, and this is reviewed. Diverse patterns of disease exist with respect to clinical, radiologic, pathologic findings and these are driven by unique molecular events, the mechanisms and origin of which are increasingly determined to be due to stochastic events. Consequently, mesothelioma has not only considerable radiologic, macroscopic, and microscopic heterogeneity, but includes multiple distinct genetic entities. Most mesotheliomas are characterized by recurrent mutations in tumor suppressor genes and epigenetic regulators, including <i>BAP1, NF2, TP53, SETD2</i>, and other genes. Alterations are identified in multiple pathways in the regulation of cell-cycle, RNA processing, histone regulation, and cell growth. <i>BAP1</i> is one of the most frequently altered genes and is activated by diverse mechanisms including <i>BAP1</i> point mutations, copy number loss, inactivating structural rearrangements, and minute chromosomal deletions. Consistent with its histomorphologic heterogeneity, mesothelioma displays an impressive molecular diversity. Subsets of mesothelioma have unusual genetic alterations: genomic near-haploidization in rare pleural mesotheliomas with mutations in <i>TP53</i> and/or <i>SETDB1</i>; oncogenic <i>EWSR1-ATF1</i> fusion; <i>ALK</i> rearrangements in rare patients with peritoneal mesothelioma. In addition, germline mutations are present in a subset of patients with mesothelioma and primarily involve genes in the DNA repair and cell cycle regulation and are more common in patients who are young, with family history of mesothelioma, or with peritoneal mesothelioma. In this review, we discuss the considerable heterogeneity of mesothelioma, the diversity of radiologic and gross presentation, various morphologic features with distinctive histologies and ultimately, we individually describe subsets of tumors characterized by uncommon alterations such as germline mutations, genomic near-haploidization, <i>ALK</i> rearrangement, <i>ATF1</i> rearrangement, or <i>EWSR1::YY1</i> fusion, as well as the implications of these findings on the diagnostic workup.