An important target of the second messenger cyclic adenosine monophosphate (cAMP) is protein kinase A (PKA). PKA, which regulates processes as diverse as growth, memory, and metabolism, exists as an inactive complex of two catalytic subunits and a regulatory subunit dimer. cAMP binds to the regulatory subunits and facilitates dissociation and activation of the catalytic subunits. Kim et al. have determined the 2.0 angstrom resolution structure of the PKA catalytic subunit bound to a deletion mutant of the regulatory subunit (RIα). The complex provides a molecular mechanism for inhibition of PKA and suggests how cAMP binding leads to activation.