In the plant pathogen Xanthomonas campestris pv. campestris (Xcc) a two component system comprising RpfG and the complex sensor kinase RpfC is implicated in sensing and responding to the cell-cell signaling molecule DSF to positively regulate the synthesis of virulence factors such as extracellular enzymes, biofilm structure and motility. RpfG is a two-component regulator with a CheY-like receiver domain attached to an HD-GYP cyclic di-GMP phosphodiesterase domain. In a recent paper we showed that that the physical interaction of RpfG with two proteins with a diguanylate cyclase (GGDEF) domain, acts to control a sub-set of RpfG-regulated virulence functions. These protein-protein interactions required the conserved GYP motif in the HD-GYP domain of RpfG and were dependent on DSF signaling. Here we discuss these findings, considering in particular different scenarios for the role of RpfG in multiple signaling pathways involving cyclic di-GMP that impinge on virulence.