Vancomycin-resistant enterococci (VRE) are among the most difficult to treat pathogens as some have evolved resistance to all available antimicrobials, including the frontline lipopeptide antibiotic daptomycin, which targets the bacterial cell membrane. Now, Khan et al. found that antimicrobial sensing coupled with cell membrane remodelling mediates resistance to daptomycin and virulence in Enterococcus faecalis. Daptomycin resistance involves the activation of the LiaFSR cell membrane stress response, which regulates cell membrane remodelling and phospholipid distribution. The authors found that the extracellular domain of LiaX binds to daptomycin or antimicrobial peptides (AMPs) and activates the stress response, resulting in protective changes in cell membrane phospholipid architecture. E. faecalis strains that exhibited LiaX-mediated cell membrane remodelling caused more virulent infections in Caenorhabditis elegans, which was dependent on the host’s ability to produce AMPs. Targeting this stress response could be a promising strategy for treating VRE infections.