Evaluation of: Di Girolamo F, Boschetti E, Chung MC, Guadagni F, Righetti PG. 'Proteomineering' or not? The debate on biomarker discovery in sera continues. J. Proteomics 74(5), 589-594 (2011). The combinatorial peptide ligand library in association with mass spectrometry can greatly enhance the dynamic range of the analysis of low- and very low-abundance proteins constituting the vast majority of species in any sample. When compared with untreated samples, the increment in detection of low-abundance species appears to be at least fourfold. Recently, the combinatorial peptide ligand library has been challenged; however, it has been clearly demonstrated in the evaluated paper that the protocols for elution of the captured polypeptides make the difference. Therefore, the solid-phase ligand library made of hexapeptides remains a promising and unique tool for biomarker discovery.