Staphylococcus aureus is a major human pathogen that is resistant to numerous antibiotics in clinical use. We found two nonribosomal peptide secondary metabolites-the aureusimines, made by S. aureus-that are not antibiotics, but function as regulators of virulence factor expression and are necessary for productive infections. In vivo mouse models of bacteremia showed that strains of S. aureus unable to produce aureusimines were attenuated and/or cleared from major organs, including the spleen, liver, and heart. Targeting aureusimine synthesis may offer novel leads for anti-infective drugs.