Malignant mesothelioma (MM) is a rare, aggressive solid tumor with limited therapeutic options and poor therapeutic response. The role of immunotherapy in MM is now well established and therapeutic options, such as checkpoint inhibitors, are increasingly being approved. Chimeric antigen receptor (CAR)-T cell therapy is successfully implemented in several hematologic cancers, but currently has inadequate effect in solid tumors, owing to several limitations, such as trafficking and infiltration, limited T cell persistence and exhaustion, the immunosuppressive TME and tumor antigen heterogeneity. The lack of uniform and universal expression of tumor-associated antigens (TAAs) on tumor cells, as well as TAA heterogeneity following tumor editing post-therapy, are issues of significant importance to CAR-T cell and associated antigen-targeting therapies. Our review discusses the concept of tumor antigen heterogeneity in MM, the consequences for CAR-T cell therapies and the strategies to overcome it.