The discovery of clinically relevant biomarkers using gel-based proteomics has proven extremely challenging, principally because of the large dynamic range of protein abundances in biofluids such as blood and the fact that only a small number of proteins constitute the vast majority of total blood protein mass. Various separation, depletion, enrichment, and quantitative developments coupled with improvements in gel-based protein quantification technologies, specifically fluorescence two-dimensional difference gel electrophoresis (2D-DIGE), have contributed to significant improvements in the detection and identification of lower abundance proteins. One of these enrichment technologies, ProteoMiner, is the focus of this chapter. The ProteoMiner technology utilizes hexapeptide bead library with huge diversity to bind and enrich low-abundance proteins but at the same time suppresses the concentration of high-abundance proteins in subsequent analysis.