Restriction–modification (R–M) systems are commonly used by bacteria to defend against invading DNA. In these systems, a methyltransferase methylates endogenous DNA as a marker of 'self' and a cognate restriction enzyme cleaves invading DNA that lacks this modification. Guet and colleagues asked whether R–M systems ever err in the discrimination between self and non-self DNA, and whether such an error would incur a fitness cost. Testing the EcoRI and EcoRV R–M systems in Escherichia coli, they found that EcoRI, but not EcoRV, measurably, and stochastically, targets self DNA, albeit at a low frequency. The difference between EcoRI and EcoRV was attributed to a more efficient restriction enzyme, which makes for a more potent defence against foreign DNA but also increases the chance of cleaving self DNA prior to modification. However, fitness costs were minimal; E. coli cells growing at steady-state efficiently repaired EcoRI-mediated DNA damage and the induced SOS response was transient and did not affect cell viability.