<p>Environmental health research has historically focused on associations between criteria air pollutants—particularly particulate matter—and health outcomes. Although these studies have established critical links between regulated pollutants and adverse effects, they fail to capture the multidimensional nature of the human airborne exposome. The air comprises thousands of organic compounds, dozens of inorganic substances and millions of microorganisms that are breathed in, leading to personalized exposure profiles. This current paradigm has three limitations: statistical challenges in analysing multi-pollutant data; inadequacies in exposure assessment; and knowledge gaps in biological mechanisms. Here a new research framework is proposed, which integrates mixture-based analytical approaches, advanced personal monitoring technologies and multi-omics methods. This framework would illuminate the aetiology of complex diseases with multifactorial environmental components, such as cancers, neurological disorders and immune dysregulation. By better characterizing individual-level exposures and biological responses, this approach could enable precision interventions that protect vulnerable populations with unprecedented specificity.</p>