Malignant mesothelioma is characterized by its association with asbestos, its long latency period, and the propensity for the diagnosis to be obtained in the later stages of the disease. Because the high-risk cohorts for mesothelioma are fairly well defined by the association with asbestos, and the exposure is usually in the workplace, it is hypothesized that early detection of the disease could (1) find patients at an earlier, more treatable stage and (2) result in prolonged survival over the present median 12 months from the start of therapy. Many studies have used standard chest X-ray to characterize changes associated with asbestos-exposed individuals, but the insensitivity of X-ray in screening patients with mesothelioma has never supported the wide-scale adaptation of such an effort. With the advent of computerized tomography, prospective trials, many of which are chiefly prevalence detection studies, have been performed and stress the importance for proper detailing by carefully qualifying suspicious changes, as well as defining the correct cohort to screen. Most recently, serum biomarkers with the potential to discriminate asbestos-exposed, non-cancer-bearing individuals from those with mesothelioma have been investigated both at single institutions and with multi-institutional-blinded trials. These markers, including soluble mesothelin-related protein, osteopontin, and megakaryocyte potentiating factor, may, in the future, be incorporated into a screening algorithm for high-risk asbestos-exposed individuals to help monitor these cohorts in a noninvasive fashion and guide the use of computerized tomography.