A biomarker is defined as a biological substance (i.e., protein, metabolite, specific post-translational modification) that can be used to detect a disease, measure its progression or the effects of a treatment. Importantly, a biomarker should be readily accessible (i.e., present within body fluids); it must also provide sufficient sensitivity and specificity to accurately distinguish between true positives, false positives, and false negatives. Even more importantly, detection of the biomarker should provide clinical benefits to the patient (i.e., improved survival and/or quality of life). Due to recent technical advances in biomolecular mass spectrometry, a great deal of effort has gone into the discovery of biomarkers at an international level. In this commentary we set forth our views on how mass spectrometry (MS) could be applied to the discovery of elusive biomarkers (Figure 1).