Malignant pleural mesothelioma is a highly aggressive tumour associated with asbestos exposure. There are few effective treatment options for mesothelioma and patients have a very poor prognosis with a median survival of less than 12 months from diagnosis. Biomarkers have been proposed as a cost-effective means of cancer management and the search for a mesothelioma biomarker has been on-going for the past thirty years. Many traditional soluble (glyco)-protein biomarkers have been evaluated over this time and an ever increasing list of new biomarkers, including mRNA, DNA, miRNA and antibodies, are being reported from biomarker discovery projects. To date, soluble mesothelin is the only tumour biomarker to receive FDA approval for clinical use in mesothelioma. Mesothelin is a glycoprotein normally expressed on the surface of mesothelial cells, and in the cancerous state can be present in the circulation. Mesothelin has a limited expression on normal, non-malignant tissue and is thus an attractive therapeutic target for mesothelin-positive tumours. In this review we will focus on the discovery and clinical usages of mesothelin and provide an update on other mesothelioma biomarkers and show how such biomarker studies might impact on the management of this deadly tumour in the future.