Due to occupational asbestosis exposure, the incidence of malignant pleural mesothelioma (MPM) has continuously increased over the last 30 years, with a plateau anticipated around the year 2030 in Western countries. Molecular MPM carcinogenesis involves alterations of NF2, RASSF1, LATS2WT1, p16, as well as BAP-1tumor-suppressor genes, which usually regulate apoptosis, cell invasion, motility, cell division, chromatin remodeling, as well as control of DNA repair. In few selected patients, debulking surgery consisting of pleurectomy-decortication is carried out, resulting in unsatisfactory long-term results. For about 15 years, first-line chemotherapy has been primarily based on a doublet of pemetrexed and cisplatin. Adding the monoclonal antibody bevacizumab (Avastin^®), which targets vascular endothelial growth factor (VEGF), has been shown to improve overall survival (OS) by nearly 19 months. The emergence of immune check-point inhibitors (ICIs) in MPM treatment has recently been associated with substantial survival improvements in both second- and first-line settings. Similarly to non-small-cell lung cancer (NSCLC) patients, on-going trials are presently exploring the chemotherapy-ICI combination in MPM management, and depending on their results, this combination could represent a further major advance in this previously orphan disease. The current article reviews recent clinical trial results, as well as future clinical developments in this moving field.