Redox reactions between polyoxometalates (POMs) and biologically relevant molecules have been virtually unexplored but are important, considering the growing interest in the biological applications of POMs. In this work we give a detailed account on the redox behavior of Ce-IV-substituted polyoxometalates (Ce-IV-POMs) toward a range of amino acids and peptides. Ce-IV-POMs have been shown to act as artificial proteases that promote the selective hydrolysis of peptide bonds. In presence of a protein, a concomitant reduction of Ce-IV to Ce-III ion is frequently observed, leading us to examine the origins of this redox reaction by first using amino acid building blocks as simple models. Among all of the examined amino acids, cysteine (Cys) showed the highest activity in reducing Ce-IV-POMs to Ce-III-POMs, followed by the aromatic amino acids tryptophan (Trp), tyrosine (Tyr), histidine (His), and phenylalanine (Phe). While the redox reaction with Cys afforded the well-defined product cystine, no oxidation products were detected for the Trp, His, Tyr, and Phe amino acids after their reaction with Ce-IV-POMs, suggesting a radical pathway in which the solvent likely regenerates the amino acid. In general, the rate of redox reactions increased upon increasing the pD, temperature, and ionic strength of the reaction. Moreover, the redox reaction is highly sensitive to the type of polyoxometalate scaffold, as complexation of Ce-IV to a Keggin (K) or Wells-Dawson (WD) polyoxotungstate anion resulted in a large difference in the rate of redox reaction for both Cys and aromatic amino acids. The reduction of (CeK)-K-IV was at least 1 order of magnitude faster in comparison to (CeWD)-W-IV, in accordance with the higher redox potential of (CeK)-K-IV in comparison to (CeWD)-W-IV. The reaction of (CePOMs)-P-IV with a range of peptides containing redox-active amino acids revealed that the redox reaction is influenced by their coordination mode with Ce-IV ion, but in all examined peptides the redox reaction is favored in comparison to the hydrolytic cleavage of the peptide bond.