The cancer biomarker field appears to be stagnant. Very few, if any, new cancer biomarkers have been introduced into clinical practice the last 20 years. The reason is that most of the newly discovered cancer biomarkers are inferior in terms of sensitivity and specificity to the classical cancer biomarkers that we currently use. The revolutionary technologies of proteomics, genomics, and other omics did not deliver on the promise to discover new and improved cancer biomarkers. However, more recently, the explosive growth of whole genome and exome sequencing has provided for the first time nearly complete mutational landscapes of many cancer types, in thousands of samples. We now know that many of these mutations are only found in cancer. It is thus possible that the mutant proteins encoded by these genes may represent the long-sought, highly specific cancer molecules that we may envision to use as cancer biomarkers. I here speculate that modern mass spectrometry may have the necessary sensitivity and specificity to detect mutant proteins in various biological fluids for the purpose of diagnosis, prognosis, and disease monitoring.