The metabolites in safety testing and ICH-M3 guidance documents emphasize the importance of metabolites when considering safety aspects for new drugs. Both guidances state that relevant metabolites should have safety coverage in humans (although the guidelines have different definitions of relevant metabolites). Not having safety coverage for important metabolites in humans may cause significant delay in the overall pharmaceutical development program. This article discusses the regulatory background regarding safety and metabolites, as well as outlines an integrated strategy taken by one pharmaceutical company, Lundbeck A/S. Lundbeck uses metabolite exposure data from first-in-man studies, obtained using an accelerator MS approach followed by a two-tiered bioanalytical investigation. This enables early availability of key data on this aspect and, overall, represents a powerful risk mitigation strategy.