Asbestos exposure is the main cause of mesothelioma. After these fibers are breathed in, they travel to the ends of small air passages and reach the pleura where they cause physical damage to mesothelial cells that may result in cancer. In addition, they also cause injury to lung cells that can result in lung cancer and/or asbestosis (replacement of lung tissue by scar tissue). If swallowed, these fibers can reach the abdominal cavity where they have a role in causing peritoneal mesothelioma.

Exposure to asbestos, though mostly occupational, can also be environmental, or familial by household contamination, through the work clothes of an asbestos worker for instance.

Beginning 15 years after the onset of exposure, about 6% of asbestos workers die of mesothelioma. In one study of asbestos insulation workers, the death rate from mesothelioma was 344 times higher than in the general population.