1H NMR spectroscopy was applied to study the reactions of palladium(II) complexes, cis-[Pd(dpa)Cl 2] and cis-[Pd(dpa)(H 2O) 2] 2+ (dpa is 2,2′-dipyridylamine acting as a bidentate ligand) with the dipeptides methionylglycine (Met-Gly) and histidylglycine (His-Gly), and the N-acetylated derivatives of these dipeptides, MeCOMet-Gly and MeCOHis-Gly. All reactions were carried out in the pH range 2.0–2.5 with equimolar amounts of the palladium(II) complex and the peptide at two different temperatures, 25 and 60 °C. In the reactions of cis-[Pd(dpa)Cl 2] and cis-[Pd(dpa)(H 2O) 2] 2+ with Met-Gly and His-Gly, no hydrolysis of the peptide bond was observed. The final product in these reactions was the [Pd(dpa) 2] 2+ complex. The square-planar structure of this complex was confirmed by X-ray analysis. The reaction of the cis-[Pd(dpa)(H 2O) 2] 2+ complex with the MeCOHis-Gly and MeCOMet-Gly peptides under the previously mentioned experimental conditions was remarkably selective in the cleavage of the amide bond involving the carboxylic group of methionine in the side chain. The modes of coordination of cis-[Pd(dpa)Cl 2] and cis-[Pd(dpa)(H 2O) 2] 2+ in the reactions with the non-acetylated peptides and the total steric inhibition of the hydrolytic reaction between cis-[Pd(dpa)(H 2O) 2] 2+ and MeCOHis-Gly can be attributed to the steric bulk of the palladium(II) complex. This finding should be taken into consideration in designing new palladium(II) complexes for the regioselective cleavage of peptides and proteins.