The distinct character of the two calmodulin (CaM) domains is reflected in different calcium and target interaction affinities, with the C-terminal domain generally showing the higher affinities. We address the distinct properties and roles of the CaM domains by using computer simulations to examine the relative flexibility of the two domains. We used extensive molecular dynamics simulations of the individual domains to sample their conformational space. From this sample of conformations, we performed multiple normal-mode analyses to compute vibrational and thermodynamic properties. We see higher intrinsic flexibility of the C-domain compared with that of the N-domain. Furthermore, in a simulation of a CaM-target peptide complex, the C-domain conformation maintains its conformation better and has lower atomic RMS fluctuations than the N-domain. These results tie in with the observed differentiation of roles of the CaM domains.