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Cyclic nucleotides are ubiquitous signaling molecules that are present in life forms ranging from bacteria to yeast to humans. In higher eukaryotes, conserved molecular machinery processes signals through both cyclic adenosine monophosphate (AMP) and cyclic guanosine monophosphate (GMP). Hurley describes how one widespread cyclic nucleotide recognition module, the GAF (cyclic GMP, adenylyl cyclase, FhlA) domain, formerly thought to bind only cyclic GMP, has now been found to bind cyclic AMP as well. Recent structural analysis of a cyclic GMP-binding GAF domain shows how conserved elements among the cyclic nucleotide-binding subgroup of GAF domains recognize the common chemical moieties in the two compounds.