The second messenger cyclic di-GMP, which is involved in many different aspects of bacterial physiology and development, is synthesized by GGDEF-domain diguanylate cyclases (DGCs) and degraded by EAL- or HD-GYP-domain phosphodiesterases (PDEs). Although the DGCs and EAL PDEs have been intensively investigated, much less is known about the HD-GYP PDEs. Bellini et al. now describe the crystal structures of a catalytically active HD-GYP domain protein alone and in complex with its cyclic di-GMP substrate and the final reaction product, GMP. The structures show that the mode of substrate binding differs from that of the EAL PDEs and involves a novel trinuclear, rather than a binuclear, catalytic iron centre.