The increasing number of malignant pleural mesothelioma (MPM) is a serious public health problem. The prognosis of this tumor is poor and most of the patients are diagnosed late in the disease's course when curative treatment is no more an option. It is therefore necessary to diagnose earlier MPM in these patients in order to obtain a potential significant improvement in survival. Some serum markers have been previously proposed for MPM diagnosis but none had sufficient sensitivity and specificity for being use in routine. Recently, soluble mesothelin and osteopontin have been proposed as diagnostic markers for mesothelioma. The authors reviewed recent data concerning the utility of these two molecules in the diagnosis and the treatment of MPM. Mesothelin seems to be a specific marker for the epithelioid subtype of mesothelioma. Despite a good sensitivity, osteopontin has a low specificity for mesothelioma diagnosis. However, there is not enough data yet to propose guidelines on the use of these markers in a day to day practice.