Cre and CreER mouse strains are powerful tools that have proven invaluable for investigating the function of genes and for the fate-mapping of cell populations. The fidelity of these systems however are becoming more and more contested. In this issue of the European Journal of Immunology, Van Hove et al. and Chappell-Maor et al. carefully dissect the cellular specificities of two commonly used CreER mouse strains for the study of CNS macrophages; Cx3cr1CreER and Sall1CreER . Both studies elegantly highlight that CreER strains, as well as the "floxed" allele to be targeted, need to be carefully selected and properly characterized in order to ensure reproducible and robust data and interpretations. These studies are a cautionary tale for this technology, but also highlight that we must continuously question and improve our experimental approaches. © 2020 The Authors. European Journal of Immunology published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.