Simple SummaryThis review article will focus on the landmark studies that came to define current treatment paradigms for malignant pleural mesothelioma (MPM), all the way from standard chemotherapy to ongoing clinical trials with immunotherapy combinations, along with some of the most novel approaches currently under investigation. Malignant pleural mesothelioma remains an orphan disease, but current and future scientific advancements hold promise for an increased chance of survival and continued quality of life for the thousands of patients diagnosed yearly with this illness. Most recently, in 2022, immune checkpoint blockade has been FDA-approved as first-line therapy for advanced malignant pleural mesothelioma (MPM).AbstractMalignant pleural mesothelioma (MPM) is a malignancy associated with asbestos exposure and is typically categorized as an orphan disease. Recent developments in immunotherapy with anti-PD-1 and anti-CTLA-4 antibodies, specifically with agents nivolumab and ipilimumab, have demonstrated an improvement in overall survival over the previous standard chemotherapy leading to their FDA-approval as first-line therapy for unresectable disease. For quite some time, it has been known that these proteins are not the only ones that function as immune checkpoints in human biology, and the hypothesis that MPM is an immunogenic disease has led to an expanding number of studies investigating alternative checkpoint inhibitors and novel immunotherapy for this malignancy. Early trials are also supporting the notion that therapies that target biological molecules on T cells, cancer cells, or that trigger the antitumor activity of other immune cells may represent the future of MPM treatment. Moreover, mesothelin-targeted therapies are thriving in the field, with forthcoming results from multiple trials signaling an improvement in overall survival when combined with other immunotherapy agents. The following manuscript will review the current state of immune therapy for MPM, explore the knowledge gaps in the field, and discuss ongoing novel immunotherapeutic research in early clinical trials.