Nestin-Cre mice have a significant metabolic phenotype that is hard to discern from current literature. Indeed, the Cre-lox system has numerous problems that can affect physiological parameters, and these are missed when the correct control strains are not used. Despite the increasing use of the Cre-lox system, these issues were not visible to the scientific community previously and may have affected published work. This makes it important to highlight the issues and raise awareness of the pitfalls of the Cre-lox system. Therefore, this perspective will discuss the impact of CNS and peripheral "off-target" Cre recombination on metabolic systems and describe the development of new approaches to obviate the difficulties.