It is increasingly recognized that the genetic background (i.e., all genomic sequences other than the gene(s) of interest) can have profound influences on the phenotype of an animal model. It has been shown that mutations (spontaneous and induced), transgenes, and targeted alleles (knockouts and knockins) that are moved onto a different background can show a change in phenotype. One of the first cases involved the classical diabetes (Leprdb) mutation that presented transient diabetes on a C57BL/6 background but overt diabetes on C57BLKS. Other examples include background effects on survival rate in Egfr (epidermal growth factor receptor) KO mice and effects on tumor incidence and spectrum in Trp53 and Pten (tumor suppressors) KO mice. In order to highlight the importance of this issue, I will present a selection of published articles showing the influence of genetic background on different mouse and rat models. I will also discuss some of the problems arising from the use of undefined substrains, the use of genetically engineered mice with mixed backgrounds (e.g., after breeding chimeras), as well as the flanking genes and passenger mutations concerns. Finally, I will present different ways to avoid or resolve these drawbacks, including the development of congenic strains by marker-assisted backcrossing and the use of newly available ES cells from strains other than 129. In order to stay away from confounding or unreliable experimental results, particularly with the increasing number of mouse and rat strains, attention to the genetic background is crucial.