Mesothelioma is a lethal cancer of the serosal lining of the body cavities. Risk factors include environmental and genetic factors. Asbestos exposure is considered the principal environmental risk factor, but other carcinogenic mineral fibers, such as erionite, also have a causal role. Pathogenic germline (heritable) mutations of specific genes, especially BAP1, are thought to predispose the individual to mesothelioma in about 10% of cases. Somatic mutations and deletions of specific tumor suppressor genes, particularly BAP1, CDKN2A/B, and NF2, occur frequently in human mesothelioma, and asbestos-exposed mice with heterozygous deletions of any one of these genes have been shown to develop mesothelioma more often and at an accelerated rate than in control animals. Autochthonous mesothelioma mouse models, which are genetically engineered to carry multiple genetic lesions matching those observed in the human disease counterpart, closely resemble the disease phenotype and the extensive inflammatory responses that characterize human mesothelioma. Because autochthonous mice do not require asbestos exposure and form tumors rapidly, these models are invaluable for assessing novel therapeutic strategies in an immunocompetent setting. The overlapping genetic, epigenetic, and immune environments of the tumors observed in these genetically engineered mouse models (GEMMs) and human primary mesothelioma specimens support the clinical relevance of these preclinical models. This article presents protocols for studies of asbestos-induced mesothelioma in GEMMs and non-carcinogenic conditional knockout models of mesothelioma, including an example of a preclinical application. These models are invaluable for understanding the biological underpinnings of mesothelioma and for testing new therapeutics and chemoprevention or interception agents. © 2025 Wiley Periodicals LLC. Basic Protocol 1: Generation of a genetically engineered mouse model (GEMM) with a germline Bap1 knockout allele Basic Protocol 2: Generation of GEMMs with germline Bap1 knock-in alleles Basic Protocol 3: Asbestos carcinogenicity investigations with GEMMs Basic Protocol 4: Preclinical chemoprevention and chemotherapy studies using a GEMM with asbestos-induced mesothelioma Basic Protocol 5: Generation of a GEMM with conditional knockout of Bap1 Basic Protocol 6: Generation of a conditional knockout model of mesothelioma.