Malignant mesothelioma is an aggressive tumour, with a poor prognosis and an increasing incidence as a result of widespread exposure to asbestos. The results of the treatments available are poor. Surgery and radiotherapy have a limited role in highly selected patients and systemic therapy is the only potential treatment option for the majority of patients. Despite some definite activity of the novel antifolates such as pemetrexed and raltitrexed, the results, even in combination with platinating agents, are still modest, with a median survival of approximately one year. The better understanding of the biology of mesothelioma makes the assessment of a number of targeted agents particularly interesting. Unfortunately, the targeted agents imatinib, gefitinib, erlotinib and thalidomide have been shown to be ineffective in unselected patients. Studies with anti-angiogenesis agents are ongoing. An improvement of the knowledge of major molecular pathways involved in malignant mesothelioma is needed in order to define proper targets for the systemic treatment of this disease.