Recent work on the structure and dynamics of the Fe–CO and Fe–O2 bonds in carbonmonoxy myoglobin (MbCO) and oxymyoglobin (MbO2), respectively, is summarized. The calculations are performed by means of a hybrid QM/MM method based on Density Functional Theory (DFT) combined with the CHARMM force-field (J. Chem. Phys.1999, 110, 10452). The results shed light into the long standing question of whether the myoglobin discriminates the CO ligand with respect to O2 by distorting the FeCO bond. It is shown that both in the gas phase and in the protein the Fe–CO bond is essentially linear and therefore the hypothesis that the CO in MbCO is sterically hindered is excluded. In contrast, hydrogen bonding between the O2 ligand and the His64 residue easily explains the protein discrimination for CO.