A common way to manipulate and to study a gene of interest in vivo uses a tissue-specific promoter to drive the expression of the Cre recombinase. Heffner et al. used a LacZ colourimetric reporter to characterize the tissue distribution of Cre activity in 40 mouse Cre strains during embryogenesis and adulthood. They found various features indicating that caution is required when interpreting phenotypes from these strains: off-target Cre activity in multiple tissues, variability in expression between littermates and differential activities of maternally versus paternally inherited Cre alleles. The authors plan to extend these analyses to more of the 365 strains in The Jackson Laboratory Cre repository.