It has been suggested that bactericidal compounds, including aminoglycoside antibiotics and hydroxyurea, kill bacteria through activation of the Cpx system and subsequent formation of reactive oxygen species. The two-component Cpx system involves the kinase–phosphatase CpxA sensing and tranducing stress signals to its regulator, CpxR, through phosphorylation, leading to transcriptional activation; the response is inactivated by CpxA-mediated dephosphorylation of CpxR. Here, the authors show that Cpx can actually protect bacteria from aminoglycosides and hydroxyurea. Bacteria carrying a mutant CpxA that lacks phosphatase activity (and thus constitutively activates the Cpx response) were protected from aminoglycosides and hydroxyurea. However, these bacteria did not show enhanced resistance to fluoroquinolones and β-lactams, indicating that not all bactericidal antibiotics kill by the same mechanism.