Profiling of differentially expressed proteins is perhaps the most important and useful approach in developing tools for risk assessment in a population, diagnostic screening, and therapeutics. Proteomic markers have potential for identifying individuals at high risk of developing cancer; however, these markers have not been extensively used in cancer epidemiologic studies. Several markers have to be clinically validated. In this chapter, methods used in proteomic analysis of clinical samples, challenges in the proteomics and cancer epidemiology, and their potential solutions are discussed.