Multimodality treatment of malignant pleural mesothelioma (MPM) with surgery, radiation therapy, and adjuvant or neoadjuvant chemotherapy is the sole path to extended survival for select patients with favorable prognostic factors. No single-modality approach has produced equivalent results. Much effort has been expended since first recognition of this insidious pleural cancer to elucidate the underlying cause and optimal treatment strategy. Despite recent breakthroughs, the principal barrier to achieving a cure rests with the propensity for disease recurrence in the ipsilateral hemithorax. Despite these limitations, however, the results hold promise for improved survival with further refinement in patient selection and targeted therapy. Other approaches to multimodality treatment have capitalized on an array of innovative technologies in search of the silver bullet strategy that will ultimately undermine the biological behavior demonstrated by MPM. These range from the use of different means of radiation delivery, biological agents, virally mediated gene therapy, photodynamic therapy, and immunotherapy. Additionally, studies using gene ratios will yield more accurate means by which to diagnose, distinguish prognosticators, and more selectively assign patients to aggressive treatments. In light of the current worldwide epidemic, the lessons learned over the past several decades serve as a humbling reminder of the treatment barriers that remain.