The immune system responds to many substances present in our environment, as well as lifestyle factors such as lack of exercise or Western-type diets. These factors, as well as natural products in the wrong concentration, can trigger inadequate immune reactions leading to chronic low-grade inflammation, also called metaflammation. Single cell omics (SCO) technologies have the great potential to revolutionize our understanding of biological processes, including metaflammation. The ability to measure heterogeneous cell populations and their responses to exogenous stimuli in a single experiment on the single cell level allows to answer novel important questions, such as which cell types and subsets truly react to the stimulus, are different cell types reacting with cell type-specific responses or are there overarching signalling pathways involved, and what is the cell-to-cell communication between different cells during stimulation? To better understand such cellular and molecular complexity during inadequate immune responses triggered by metaflammation-inducing substances in humans, we propose to 1) develop a whole blood-based compound incubation assay for single cell omics analysis to identify compounds that might induce metaflammation, 2) to prototypically uncover the cell types and molecular pathways involved in metaflammation induced by AhR ligands and newly identified bioactive substances derived from unbiased analyses of Western diet-fed animals, 3) to perturb major pathways, particularly central transcription factors, potentially involved in metaflammation, and 4) to translate this approach to a clinical setting allowing the assessment of individual reactivities to environmental metaflammation-driving compounds. We propose that our studies will trigger additional studies targeting individual molecular pathways and cell subsets, allowing for a better understanding of the interplay between different cell states and molecular pathways. The simultaneous assessment of thousands of parameters in thousands of cells by SCO will greatly expedite our ability to capture the multiple changes happening during such complex mechanisms as they are expected for metaflammation. We will continuously provide technological as well as scientific insights derived from CRC to all our collaborators within the CRC. Third, we envision to develop a clinically applicable (bedside) test based on SCO that would allow to probe an individual’s immune reactivity towards several dozen environmental compounds for inducing metaflammation. We foresee such clinical tests as future cornerstones for the assessment of immune functionality, similar to what an ECG is for a cardiologist. Such tests will be necessary to predict and describe immune deviations in acute and chronic inflammatory diseases within our societies.