Malignant pleural mesothelioma (MPM) is recalcitrant to treatment and new treatments are urgently needed. Multiple genes involved in proliferation and metabolic activity are upregulated in MPM and these represent attractive targets for an siRNA-based intervention. We carried out an RNAi-based screen of 40 target genes to identify candidate genes with roles in cell growth and survival in MPM cells. All 40 genes were effectively silenced, and for 6 genes knockdown with 2 independent siRNAs resulted in significant growth inhibition over time in multiple cell lines: PLK1, CDK1, NDC80, RRM1, RRM2 and BIRC5 (Survivin). Dose response experiments with varying concentrations of siRNA revealed that siRNAs specific for RRM1 and RRM2 were the most effective at inhibiting growth with IC50 values in the low nanomolar range. A chemically modified siRNA targeting RRM1 was selected for in vivo studies in a xenograft model of MPM. Intravenous administration of RRM1 siRNA packaged in minicells targeted with EGFR-specific antibodies (2x109 minicells per dose, 4 times per week for 3 weeks) led to consistent and dose-dependent inhibition of MPM tumor growth compared with treatment with an inactive siRNA. Reducing the dose and number of administrations did not reduce growth inhibition; as little as 1x109 minicells administered once a week were sufficient to completely inhibit MPM tumour growth. In conclusion, RRM1 is an attractive target for siRNA-based inhibition, and siRNA delivery with EGFR-targeted minicells represents a novel therapeutic approach for MPM.