Cyclic nucleotide binding domains (CBDs) regulate proteins that are involved in a wide range of cellular functions, including protein kinase A (PKA), protein kinase G (PKG), the exchange protein directly activated by cAMP (EPAC), and the hyperpolarization-activated cyclic nucleotide-modulated (HCN) and cyclic nucleotidegated (CNG) ion channels. Although it is known that cyclic nucleotide binding to CBDs leads to perturbations that promote the activation of key functions within the respective host proteins, the role played by dynamics in the cyclic nucleotidedependent activation is currently not fully understood. Therefore, an in-depth analysis of dynamics is essential to achieve a more complete understanding of CBD function and to fully exploit the potential of CBDs as therapeutic targets.