PM proteins have attracted significant attention as biomarkers for disease diagnosis, prognosis, monitoring, and treatment benefit prediction. In addition, they may serve as potential targets for drug therapy, a fact already proven as two-thirds of all drugs targeting proteins are directed against PM proteins. However, PM proteins are hydrophobic and possess a variety of PTMs, which require more sophisticated proteomics methods for their separation and identification. Although most proteomics studies of PM proteins are currently using cell lines, newer proteomics strategies for PM biomarker identification in clinical tissue samples, such as tumors, are being developed. Future effort should focus on optimizing these strategies and performing MS-based proteomics on clinically well characterized tissue samples. Study design is essential to effectively address the clinical problem in question, including selection of proper patient materials and sufficient numbers of samples stored under optimal conditions. These efforts require close collaborations between translational researchers, biostatisticians, pathologists, and clinicians. Moving markers from the discovery phase to daily clinical practice is also a crucial area. It is a cumbersome process that requires marker verification, validation and assay development, and testing of large numbers of clinical samples, but these efforts should determine the clinical utility of proteomics in cancer patient care.