In the past, there has been a tendency to think of diffuse malignant pleural mesothelioma as one disease in therapeutic terms, regardless of histological type and tumor stage. This does not happen with other tumors, yet it is equally illogical and inappropriate in mesothelioma. As with other tumors, early diagnosis-while the disease is still in stage I, or even at an in situ stage-must be the goal so that therapy can be maximized, particularly if immunotherapy or gene therapy is to be used. Patients with pure epithelial mesothelioma have a better prognosis and respond better to trimodality therapy. Stage I patients who meet fitness criteria should be offered the option of radical surgery in combination with chemotherapy and radiotherapy. Further research is required to determine the optimum neoadjuvant and adjuvant modalities, particularly the timing of individual drugs, use of hyperthermia, and route of administration. The place of immunotherapy and gene therapy as adjunctive treatments also remains to be defined. For example, it may be possible to reduce tumor bulk and perhaps downstage the disease with immunotherapy before radical surgery, if treatment is started early enough. Gene therapy may have a role either preoperatively or in destroying the microscopic disease that remains after radical surgery. These and other combinations of treatment need to be tested in well-designed clinical trials, probably on a multicenter basis (to enroll a sufficient number of patients). Finding the means to improve treatment for sarcomatous and mixed histology mesothelioma remains a challenge. At present, radical surgery does not seem worthwhile for these patients when combined with currently employed chemotherapy and radiotherapy; however, chemotherapy combinations used for treating other sarcomas need to be evaluated as adjunctive therapy before radical surgery is abandoned altogether as a mode of treatment. A collaborative approach involving thoracic surgeons, basic scientists and oncologists, and physicians with experience in treating mesothelioma is essential. Despite its increasing frequency, mesothelioma is still a relatively rare tumor, so treatment should be concentrated in relatively few supraregional centers to maximize expertise and allow innovative treatment combinations to be implemented with the greatest chance of success. Evaluation of new therapeutic approaches will be achieved more rapidly if these supraregional centers collaborate in multicenter trials. The nihilistic approach of simply waiting until the mesothelioma epidemic eventually begins to decline spontaneously in 20 or 30 years is untenable in view of the hundreds of thousands of deaths that will result if no effective treatment is found.