A new study shows that the type II CRISPR–Cas (clustered, regularly interspaced short palindromic repeats–CRISPR-associated proteins) system of the intracellular pathogen Francisella novicida downregulates the expression of an immunostimulatory bacterial lipoprotein (BLP), which increases the integrity of the cell envelope, resulting in antibiotic resistance and inflammasome evasion. Sampson et al. found that a mutant that lacked the endonuclease Cas9 was resistant to the membrane-targeting antibiotic polymyxin B, and in combination with its partner RNAs (the tracrRNA and scaRNA), Cas9 directly enhanced envelope integrity in vitro and during intracellular infection, owing, at least in part, to reduced expression of BLP. Furthermore, evasion of the AIM2–ASC inflammasome (which is activated by Toll-like receptor 2 (TLR2)) was Cas9-dependent, and the reduced virulence of the cas9-null mutant was restored in the absence of both ASC and TLR2, which demonstrates the pivotal role of Cas9 in evading innate immunity. Further to its role in adaptive immunity, this study shows that CRISPR–Cas is an important determinant of gene expression and contributes to bacterial pathogenesis.