Pollution is the largest environmental cause of disease and premature death in the world which causes an estimated nine million annual premature deaths. Owing to the exceptional longevity of highly toxic arsenic, cadmium, and mercury species in the environment, the Agency for Toxic Substances and Disease Registry (ASTDR) has ranked them within the top 7 chemicals of concern in terms of their frequency, toxicity, and potential for human exposure at national priority sites. Accordingly, the chronic exposure of human populations – including children – to these pollutants via the diet, drinking water and air is of increasing public health concern as it may be causally linked to human diseases, which have no known etiology. To unravel potential toxic metal exposure‐disease relationships, the elucidation of their bioinorganic chemistry in the bloodstream is critical as these processes determine which and how much of an absorbed toxic metal species and/or its metabolites will reach toxicological target organs. Considering the analytical complexity of this biological fluid, appropriate analytical techniques must be employed. We highlight advanced instrumental analytical approaches that can be used and provide examples of how their application has revealed new insight into the mechanisms of chronic toxicity of arsenic, cadmium and mercury species in mammals. A comprehensive understanding of the bioinorganic chemistry of individual toxic metal species is urgently needed to reassess current environmental regulations to reduce the global disease burden.