Gram-negative bacteria communicate among themselves by cell-to-cell signaling molecules that are essential not only for interaction within the cell population, but also for host–pathogen interactions during infections. Pseudomonas aeruginosa and Acinetobacter baumannii are opportunistic Gram-negative pathogens associated with a broad range of acute and chronic infections, as well as causing severe nosocomial problems. The quorum-sensing signaling system controls not only multiple virulence determinants such as the assembly of virulence factors essential for colonizing and perseverance in different environmental conditions, but also interference with the host core signaling pathways. We discuss the quorum-sensing role in host response during infections, focusing on the collision of quorum-sensing molecules with the immune response and host cell apoptosis modulation pathways. The pathways used during the infectious course could open new perspectives for the expansion of specific antimicrobial strategies based on communication control of this extremely adaptable and resistant opportunistic pathogen.