When colonies of Apis mellifera nest in tree cavities, they line the nest interior with a propolis envelope, which serves many purposes, including waterproofing and preventing fungal decay of the hive walls and helping promote stable temperature and humidity. Our research revealed and additional, important function: honey bees exploit the antimicrobial properties of resins to supplement individual immune function and fight off microorganisms and pathogens. Taking a fully integrative approach, our current research is focused on the mode of action of propolis on individual bee immunity. Our original hypothesis was that the antimicrobial properties of propolis would reduce the general microbial load within the nest cavity, reducing the need to produce antimicrobial peptides by the innate immune system of bees. Studies on the microbiota of bees reared in colonies with or without a propolis envelope revealed that propolis exposure reduced the pathogenic or opportunistic microbes and promoted the proliferation of putatively beneficial microbes that support immune function. These results indicate that propolis acts as a selective agent mitigating the microbiome structure and size, rather than a general agent affecting all microbes.