Current studies on environmental chemistry mainly focus on a single stressor or single group of stressors, which does not reflect the multiple stressors in the dynamic exposome we are facing. Similarly, current studies on environmental toxicology mostly target humans, animals, or the environment separately, which are inadequate to solve the grand challenge of multiple receptors in One Health. Though chemical, biological, and physical stressors all pose health threats, the susceptibilities of different organisms are different. As such, significant relationships and interactions of the chemical, biological, and physical stressors in the environment and their holistic environmental and biological consequences remain unclear. Fortunately, the rapid developments in various techniques, as well as the concepts of multistressors in the exposome and multireceptor in One Health provide the possibilities to understand our environment better. Since the combined stressor is location-specific and mixture toxicity is species-specific, more comprehensive frameworks to guide risk assessment and environmental treatment are urgently needed. Here, three conceptual frameworks to categorize unknown stressors, spatially visualize the riskiest stressors, and investigate the combined effects of multiple stressors across multiple species within the concepts of the exposome and One Health are proposed for the first time.