Several affinity-recognition-based polymeric materials have been developed to aid the depletion of highly abundant proteins in serum samples. Among these, cryogels with macroporous structures may be useful in the field of protein depletion. In particular, the requirement to deplete highly abundant proteins prior to proteome investigations makes cryogels attractive for researchers. In the present review, recent developments and applications of affinity-recognition-based polymeric materials and cryogels are reviewed regarding protein depletion.