Malignant pleural mesothelioma (MPM) is an extremely aggressive tumor which develops in the epithelial lining of the lungs. Exposure to asbestos is the most influential risk factor for developing this disease. Despite recent advances in the treatment of other types of cancer, patients with mesothelioma currently face a poor prognosis. Therefore, it is highly important to develop an early diagnostic method with the greatest challenge on screening techniques to detect the disease at a subclinical stage. Early detection is critical for the development of more effective therapies in these patients. Unfortunately, radiologic studies have not proven effective. Biomarkers might be a useful adjunct tool among populations previously exposed to asbestos. This review will provide an update of recent progress in serum biomarkers (osteopontin (OPN), soluble mesothelin (SM), and megakaryocyte potentiating factor (MPF)) to diagnose, detect, and monitor MPM. Of these, SM has demonstrated the greatest diagnostic potential although MPF may serve as an equal alternative. Despite recent studies, it is apparent that long-term large-cohort research is required to conclusively demonstrate the usefulness of these markers in this disease.