The human oral environment harbors one of the most diverse microbiomes, with microbial constituents that dynamically interact with hard and soft tissues as well as implanted surfaces. In this presentation, we discuss recent findings that leverage a discovery-validation pipeline and multidimensional data integration to identify unique interactions across species, kingdoms, and between host and microbes. By employing multi-scale imaging and computational analysis, we uncover spatially-structured polymicrobial and host cell-microbe assemblages in intact human saliva, which exhibit emergent functionalities. Through multi-omics analysis and experimental models, we discover motile species with previously unknown functional roles that form distinctive biofilm structures with enhanced metabolism, exacerbating disease severity in vivo. We also explore diagnostic and therapeutic implications, along with limitations and future directions.