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Malignant peritoneal mesothelioma (MPM) is a rare disease with a wide clinical spectrum. It arises from the peritoneal lining and commonly presents with diffuse, extensive spread throughout the abdomen and, more rarely, metastatic spread beyond the abdominal cavity. Computed tomography, magnetic resonance imaging and positron-emission tomography are important diagnostic tools used for the preoperative staging of MPM. The definitive diagnosis is based on histopathological analysis, mainly via immunohistochemistry. In this regard, paired-box gene 8 negativity represents a useful diagnostic biomarker for differentiating MPM from ovarian carcinoma. In addition, BRCA1-associated protein-1 (BAP1) loss is specific to MPM and allows it to be distinguished from both benign mesothelial lesions and ovarian serous tumors. Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) has become an increasingly important therapeutic approach, while systemic therapies are still being developed. Histology, Ki-67, completeness of cytoreduction, age, sex, and baseline thrombocytosis are commonly used to optimize patient selection for CRS with HIPEC. Additionally, it is well recognized that, compared to other subtypes, an epithelial morphology is associated with a favorable prognosis, whereas baseline thrombocytosis predicts an aggressive biologicalbehavior. Platelets and other immunologic cytokines have been evaluated as potential novel therapeutic targets. Epigenetic modifiers, including BAP1, SETD2 and DDX3X, are crucial in mesothelial tumorigenesis and provide opportunities for targeted treatment. Overexpression of the closely interacting phosphoinositide 3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) pathways appears crucial in regulation of the malignant phenotype. The use of targeted therapies with PI3K-mTOR-based inhibitors requires further clinical assessment as a novel approach.