Malignant pleural mesothelioma (MPM) is recalcitrant to treatment and new approaches are needed. As in other cancers, MPM exhibits marked changes in the expression of microRNAs, short non-coding RNAs with an important role in gene regulation. Exploring the patterns of microRNA expression in MPM tumour samples and cell lines, we have found multiple microRNAs with the ability to serve as biomarkers, therapeutic targets, or both. This work has identified microRNA markers elevated in the blood of MPM patients, a signature of microRNAs expressed in tumours that predicts patient outcome, and a number of downregulated tumour-suppressor microRNAs. Replacing these repressed tumour-suppressor microRNAs with synthetic mimics has pronounced growth inhibitory effects on tumours, both in vitro and in preclinical models. This finding has led to a first-in-man clinical trial of microRNA replacement as a therapeutic approach for MPM patients.