Purpose <p>Heavy metal contamination represents a major global health challenge, disrupting human physiology through oxidative stress, enzyme inhibition, and neuroendocrine dysfunction. Conventional chelators such as dimercaprol (BAL), ethylenediaminetetraacetic acid (EDTA), and dimercaptosuccinic acid (DMSA) are widely used but suffer from poor selectivity, depletion of essential trace elements, and reduced efficacy in chronic exposure. This review aims to evaluate the biochemical mechanisms of heavy metal toxicity, analyze the limitations of current chelation methods, and highlight emerging alternatives with improved safety and efficacy.</p> Methods <p>A literature search of PubMed, Scopus, and Web of Science (2014–2025) identified studies on heavy metal toxicity, conventional chelation therapies, and novel detoxification strategies, including phytochemicals, nanotechnology, enzyme-assisted systems, and microbiome-based approaches.</p> Results <p>Traditional chelators remain effective in acute poisoning but are constrained by non-specificity, side effects, and limited chronic application. In contrast, phytochemical-derived chelators, nanotechnology-enabled delivery systems, enzyme-based detoxification, and microbiome-targeted interventions demonstrate enhanced specificity and reduced toxicity. Advances in molecular biology and nanomedicine further support the development of next-generation chelators with potential for personalized application.</p> Conclusions <p>While conventional chelation remains clinically relevant, its limitations necessitate innovative biochemical strategies. Future therapies should focus on integrating nanotechnology, phytochemicals, enzyme systems, and microbiome modulation into personalized treatment frameworks. These approaches offer promise for safer, more targeted, and more effective management of heavy metal toxicity.</p> Graphical Abstract <p>Created in <a href="https://BioRender.com">https://BioRender.com</a></p> <p></p>