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Summary 3′,3′‐cyclic GMP‐AMP (cGAMP) is the third cyclic dinucleotide (CDN) to be discovered in bacteria. No activators of cGAMP signaling have yet been identified, and the signaling pathways for cGAMP have been inferred to display a narrow distribution based upon the characterized synthases, DncV and Hypr GGDEFs. Here, we report that the ubiquitous second messenger cyclic AMP (cAMP) is an activator of the Hypr GGDEF enzyme GacB fromMyxococcus xanthus. Furthermore, we show that GacB is inhibited directly by cyclic di‐GMP, which provides evidence for cross‐regulation between different CDN pathways. Finally, we reveal that the HD‐GYP enzyme PmxA is a cGAMP‐specific phosphodiesterase (GAP) that promotes resistance to osmotic stress inM. xanthus. A signature amino acid change in PmxA was found to reprogram substrate specificity and was applied to predict the presence of non‐canonical HD‐GYP phosphodiesterases in many bacterial species, including phyla previously not known to utilize cGAMP signaling.