Because of a lack of effective treatments, survival from diffuse pleural mesothelioma remains poor. Many people do not think that treatments for this disease are effective. The understanding of the biology of mesothelioma relevant to the apoptosis-resistant phenotype has been slow to advance. However, this is now changing, and strategies for rational therapeutic drug development are emerging that have the potential to change the natural history and improve survival in the increasing number of patients that will be diagnosed in the next two decades. This review discusses recent developments in apoptosis biology that are specific to mesothelioma and the therapeutic implications for this aggressive cancer.