Quorum sensing (QS) systems comprise a new therapeutic target potentially substitutive or complementary to traditional antibiotic treatment of chronic diseases. One route to disrupt the previously established interrelationship between pathogenesis and QS is by blocking the dual functioning signal/receptor transcriptional regulator in some clinically relevant Gram-negative bacteria. The present review contains all reported compound types that are currently known to inhibit the QS transcriptional regulator in Gram-negative bacteria. These compounds are sub-divided into two main groups, one comprising structural analogs of the native signaling molecules and the other compounds lacking structural resemblance. Biological activity is rationalized on the basis of structure-activity relationships and structural insight into the target protein.