The recent stream of regulatory guidelines on the Safety Testing of Drug Metabolites by the FDA in 2008 and the ICH in 2009 and 2012 has cast light on the importance of qualifying metabolite exposure as part of the safety evaluation of new drugs and has provided a much needed framework for the drug safety researcher. Since then, numerous publications interpreting the practicalities of the guidelines have appeared in the literature focusing on strategic approaches and/or adaptation of modern analytical methodologies, e.g., NMR and AMS, for the identification and quantification of metabolites in the species used in preclinical safety assessments and in humans. Surprisingly, there are few literature accounts demonstrating how, in practice, a particular strategy or analytical method has been used to qualify drug metabolites during the safety evaluation of a drug during clinical development. At the same time as the initial FDA and ICH guideline releases, the neuroscience therapy area of AstraZeneca had a number of projects in clinical development, or approaching this phase, which gave the authors a scaffold upon which to build knowledge regarding the safety testing of drug metabolites. In this article, we present how the MIST strategy was developed to meet the guidelines. Pragmatic approaches have evolved from the experience learned in various projects in DMPK at AstraZeneca, Södertälje, Sweden. Our experience dictates that there is no single strategy for qualifying the safety of drug metabolites in humans; however, all activities should be tied to two unifying themes: first that the exposure to drug metabolites should be compared between species at repeated administration using the relative method or a similar one; and second that the internal regulatory documentation of the metabolite qualification should be agnostic to external criteria (guidelines), indication, dose given, and timing.