GAF domains represent one of the largest families of small-molecule binding units present in nature. The first mammalian GAF domains discovered were the cGMP-binding regulatory domains of several cyclic nucleotide phosphodiesterases (PDEs). The crystal structure of the PDE2A GAF domains has provided our first look at the architecture of the binding site for the second messenger cGMP. The topology of this site differs greatly from all other previously determined cyclic nucleotide binding sites. In PDE2A, cGMP binds to a well-defined pocket in one of the two GAF domains that is analogous to the ligand-binding pocket of the distantly related PAS domains of photoactive yellow protein and FixL. The consensus cGMP-binding motif suggests strongly that only certain GAF domains will bind cGMP. Although the detailed mechanism for how cGMP binding to the GAF domain regulates catalysis remains to be determined, recent data from a GAF domain-containing cAMP-stimulated adenylyl cyclase from Anabaena suggest a mechanism conserved across two billion years of evolution. Because of their unique ligand-binding topologies, the GAF domains of PDEs are likely to offer good new targets for rational drug design.