Malignant pleural mesothelioma (MPM) is a rare and aggressive malignant disease. Currently, the platinum doublet of pemetrexed and cisplatin is the standard first-line treatment for unresectable MPM. However, recent promising results of immunotherapy have markedly changed the landscape of MPM treatment. Further, the ongoing innovative therapeutic strategies are expected to expand the range of treatment options; however, several questions remain unanswered. First, establishing predictive biomarkers with high potency is urgently needed to optimize the patient selection process. Second, further exploration of the combination algorithm is expected to unveil more effective and safe regimens. Moreover, other dilemmas, such as the resistance mechanism of immunotherapy and the role of immunotherapy in perioperative settings, still warrant further exploration.