The combinatorial peptide ligand library (CPLL) is compared here with the immunodepletion method for evaluating their respective abilities in digging deeper and deeper into the low-abundance proteome. A recent report suggested in fact that immuno-subtraction for biomarkers discovery in sera does not perform so well, since it results in a meagre 25% increase in identified proteins compared with unfractionated plasma, leaving little capacity to sample lower abundance proteins. On the contrary, CPLLs permit from 300 to 600% increments in detection abilities, as amply demonstrated in several reports. Moreover, when dealing with large sample volumes, an amplification factor of up to four orders of magnitude for trace proteins could be demonstrated, with 80% capture efficiencies even in large (up to 1 L) sample volumes. At present, the lower detection ability of CPLLs has been evaluated at 1 ng/mL (traces of casein additives in white wines).