Glutathione transferases (GSTs) are a multigene family of ubiquitously expressed, polymorphic enzymes responsible for the metabolism of a wide range of both endogenous and exogenous substrates, play a central role in the adaptive response to chemical and oxidative stress, and are subject to regulation by a range of structurally unrelated chemicals. In this review, we present a current summary of knockout mouse models in the GST field, discussing some of the issues pertaining to orthologous proteins between mice and humans, the potential confounding issues related to genetic background, and also cover new transgenic models in the increasingly important area of humanization.