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Recent advancements in MS have made tremendous impact on the throughput and comprehensiveness of cancer proteomics, paving the way to unraveling deregulated cellular pathway networks in human malignancies. In turn, this knowledge is rapidly being translated into the discovery of novel potential cancer markers (PCMs) and targets for molecular therapeutics. Head\u2010and\u2010neck cancer is one of the most morbid human malignancies with an overall poor prognosis and severely compromised quality of life. Early detection and novel therapeutic strategies are urgently needed for more effective disease management. The characterizations of protein profiles of head\u2010and\u2010neck cancers and non\u2010malignant tissues, with unprecedented sensitivity and precision, are providing technology platforms for identification of novel PCMs and drug targets. Importantly, low\u2010abundance proteins are being identified and characterized, not only from the tumor tissues, but also from bodily fluids (plasma, saliva, and urine) in a high\u2010throughput and unbiased manner. This review is a critical appraisal of recent advances in MS\u2010based proteomic technologies and platforms for facilitating the discovery of biomarkers and novel drug targets in head\u2010and\u2010neck cancer. A major challenge in the discovery and verification of these cancer biomarkers is the typically limited availability of well\u2010characterized and adequately stored clinical samples in tumor and sera banks, collected using recommended procedures, and with detailed information on clinical, pathological parameters, and follow\u2010up. Most biomarker discovery studies use limited number of clinical samples and verification of cancer markers in large number of samples is beyond the scope of a single laboratory. The validation of these potential markers in large sample cohorts in multicentric studies is needed for their translation from the bench to the bedside. \u00a9 2010 Wiley Periodicals, Inc. 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