<p>Groundwater provides water resources for human activities, while groundwater discharge sustains river baseflow and stabilizes groundwater-dependent ecosystems. However, the release of critical substances during groundwater discharge and exploitation processes, which is accompanied by changes in their concentration, speciation, bioavailability, and health risk, inevitably impacts the health of humans and the ecological environment. The critical substances that determine the health and safety of groundwater utilization include geogenic substances, biogenic elements, anthropogenic contaminants, emerging contaminants, and pathogens. Investigation of the spatio-temporal distribution and migration-transformation pattern of these critical substances in hydro-biogeochemical cycles, and understanding of the interaction mechanisms and health risks of substances with different sources and properties during groundwater extraction or discharge processes, are the cutting-edge research areas for environmental geoscience studies. The future research priorities are: (1) to explore the migration, transformation and interaction mechanisms of critical substances; (2) to break the technical bottlenecks in real-time and high-sensitivity field monitoring methods; (3) to reveal the transformation patterns of emerging contaminants in multi-media environments; (4) to improve risk models of chronic low-dose exposure; (5) to elucidate multi-component coupling mechanisms; (6) to establish the scientific index system and the assessment model of health risk for groundwater quality evaluation; and (7) to improve our understanding of the occurrence and transport processes of co-existing contaminants during the water cycle. These studies will provide indispensable theoretical and technological support to ensure a safe groundwater supply.</p>