The ExpR/Sin quorum-sensing system of the gram-negative soil bacterium Sinorhizobium meliloti plays an important role in the establishment of symbiosis with its host plant Medicago sativa. A mutant unable to produce autoinducer signal molecules (sinI) is deficient in its ability to invade the host, but paradoxically, a strain lacking the quorum-sensing transcriptional regulator ExpR is as efficient as the wild type. We compared the whole-genome expression profile of the wild-type strain with strains missing one of the quorum-sensing regulatory components to identify genes controlled by the ExpR/Sin system throughout the different phases of the bacterial growth cycle, as well as in planta. Our analyses revealed that ExpR is a highly versatile regulator with a unique ability to show different regulatory capabilities in the presence or absence of an autoinducer. In addition, this study provided us with insight into the plant invasion defect displayed by the autoinducer mutant. We also discovered that the ExpR/Sin quorum-sensing system is repressed after plant invasion. Therefore, quorum sensing plays a crucial role in the regulation of many cell functions that ensures the successful invasion of the host and is inactivated once symbiosis is established.