Pleural mesothelioma (PM) is a rare disease, which is going to be a global medical concern in the 21st century, because of its aggressiveness, late diagnosis, and insufficient therapies. This review seeks to enhance the comprehension of medical professionals regarding the risk factors and environmental influences that contribute to the development of the disease, as well as its underlying mechanisms. In addition, we aim to provide a schematic yet thorough overview of diagnostic techniques in PM, emphasizing the significance of the immunohistochemical markers BAP1 and MTAP, with the latter serving as an almost ideal surrogate for the gold-standard diagnostic approach, FISH p16/CDKN2A deletion. The scientific world is grappling with BAP1, MTAP, and the tumour inflammatory microenvironment, because they are the key for personalized treatments and palliative care in this disease. Considering that the survival rate for patients with PM seldom surpasses five years, every moment is significant. Therefore, our article also highlights recent advancements in clinical assessments related to prognostic scoring and treatment options. PM is a complex disease, with gradual progression over decades, which requires further investigation covering the prevention, mutations, diagnosis and treatment.