Second messengers play an integral role in regulating a wide variety of pathways in response to triggers from the extracellular milieu. The intracellular second messenger cyclic diguanylate (c-di-GMP) has been shown to regulate microbial adaptation to extracellular environments in myriad ways. Primarily studied in Gram-negative bacteria thus far, c-di-GMP regulates motility, biofilm formation, virulence, and more (reviewed in references 1 to 3). Specifically, elevated c-di-GMP favors a sessile lifestyle, often stimulating biofilm formation. Conversely, reduced c-diGMPpromotesbiofilmdispersalandmotility,andlowc-di-GMP can activate virulence pathways in numerous bacterial pathogens. Incomparison,littleisknownaboutthefunctionsofc-di-GMPin Gram-positive bacteria. Determining how and under what circumstances bacteria regulate c-di-GMP levels, and the outcomes ofc-di-GMPmodulation,isimportantforunderstandingtherole ofc-di-GMPinbacterialcellsignalingandadaptationtochanging extracellular cues. Yet a full appreciation of c-di-GMP signaling pathways is often hindered by the fact that many bacterial genomesencodemultiple,sometimesseveraldozen,c-di-GMPsyn