Phosphorylation, the attachment of a phosphate group from ATP to a hydroxyl group on a Ser/Thr/Tyr group, is a universal signaling mechanism that controls almost all cellular processes. The family of enzymes, eukaryotic protein kinases (EPK), which catalyzes this process, is a large family of proteins which comprise approximately 2% of the human genome. Although diverse in their biological function, the catalytic core of all these protein kinases is highly conserved. We study the cAMP-dependent protein kinase as a prototypical EPK which regulates multiple cellular processes such a differentiation, stress response, metabolism and contraction. We use a battery of biophysical techniques, with solution NMR spectroscopy as our primary tool of interest, to understand how protein dynamics and structure govern canonical (i.e. catalytic) and non-canonical (i.e. scaffolding, binding cooperativity, etc.) function of kinases. This approach is applied to understand how disease mutants in either the kinase or its substrates alter kinase function to understand the molecular basis for human diseases such as dialated cardiomyopathy and cancer.