Mesothelioma is a rare neoplasm arising from the serosa lining the pleura, pericardium, and peritoneum. It has long been associated with asbestos exposure, and its incidence and frequency in men remain tied to asbestos utilization/exposure. The strength of this association depends on the type of asbestos fiber and the exposure dose, with a latent interval for development typically measured in decades. With the onset of asbestos regulatory efforts (1970s), mesothelioma not attributable to asbestos has increased, including those secondary to genetic mutations (BAP1, NF2), radiation, persistent serosal inflammation, and immune senescence. Diffuse mesothelioma presents as a thick growth over a serosal surface, which may be associated with an effusion and involvement of regional organs. The diagnosis depends on the gross tumor distribution, the histopathologic features, and an immunohistochemical profile compatible with mesothelioma, along with the exclusion of metastasis. The 2021 WHO classification recognizes four histologic subtypes of invasive mesothelioma (epithelioid, biphasic, sarcomatoid, and desmoplastic), mesothelioma in situ, and a category of uncommon patterns. Epithelioid mesothelioma occurs in 60–70% of cases followed by biphasic and the sarcomatoid pattern. For epithelioid mesothelioma, nuclear grading conveys prognostic value. The differential diagnosis for mesothelioma includes benign, reactive mesothelial proliferations as well as primary/secondary malignancies involving serosa. A panel of immunohistochemical stains, with acceptable sensitivity and specificity, is recommended as no single marker has sufficient sensitivity and specificity to distinguish mesothelioma from other neoplasms. The immunohistochemical diagnostic approach has changed drastically in the last decade due to the addition of claudin-4, HEG1, BAP1, and MTAP. Newer markers now allow for the diagnosis of mesothelioma in situ and securing a diagnosis of mesothelioma in cytologic specimens. Fluorescence in situ hybridization provides further diagnostic support with the detection of homozygous deletion of CDKN2A/p16INK4A. Diverse surgical modalities and/or cytoreduction therapy have been used for mesothelioma without significant positive outcomes, while immunotherapy appears as a promising tool for managing untreated and unresectable disease.