Individual bacteria communicate by the release and interpretation of small molecules, a phenomenon known as quorum sensing (QS). We hypothesized that QS compounds extruded by Photorhabdus could be interpreted by Bacillus-a form of interspecies communication. We interrogate the structure-activity relationship within the recently discovered pyrone QS network and reveal the exquisite structural features required for targeted phenotypic behavior. The interruption of QS is an exciting, nonbiocidal approach to tackling infection, and understanding its nuances can only be achieved by studies such as this.