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Malignant pleural mesothelioma (MPM) is a rare and aggressive cancer with a poor prognosis. Most patients have unresectable disease at the time of diagnosis, for which palliative chemotherapy has been the standard of care for years. Despite the effort to improve systemic treatment, the prognosis remains poor, with a median overall survival of about 17–18 months. Recently, in the CheckMate 743 trial, the combination of nivolumab and ipilimumab showed improved overall survival compared with standard chemotherapy. After years, this study has challenged the role of chemotherapy as a standard of care and positioned the chemotherapy-sparing regimen as a valid alternative in the first-line MPM setting. Several new therapies other than immune checkpoint inhibitors are under consideration and might have an impact on standard practice in the near future. This review aims to revisit the systemic treatments currently recommended and those under study, as well as to explore future perspectives.