Virtually every living cell produces and secretes nanoparticles called exosomes into the extracellular space. Exosomes play a crucial role in cell-to-cell communication, facilitated by the transfer of regulatory molecules such as microRNAs inside exosomes from donor cells to adjacent or distant recipient cells. Our laboratory was first to demonstrate that exosomes and their RNA cargos are not exclusively derived from endogenous synthesis but may also be obtained from dietary bovine milk. This presentation will discuss (1) novel protocols used to assess the bioavailability and distribution of bovine milk exosomes and their RNA cargos in humans and mice, (2) interactions between exosomes and microbiome in mice, and (3) phenotypes of dietary depletion of bovine milk exosomes in infants and mice. For example, the speaker will provide evidence that milk exosomes accumulate primarily in liver and brain, whereas distinct microRNAs have unique distribution profiles in mice. The speaker will share his findings that dietary milk exosomes alter microbial communities in the murine gut, contain and deliver immune-relevant microbial RNAs to the host, and select for single nucleotide polymorphisms and mutations in cultures of murine gut microbiota. Phenotypes of dietary exosome depletion include loss of spatial learning and memory, probably due to aberrant purine metabolism. Supported by NIFA 2015–67017–23181 and 2016–67001–25301, NIH 1P20GM104320, Egg Nutrition Center, Gerber Foundation, USDA Hatch & Multistate W3002, and the U. Nebraska President’s Office. J. Z. is a consultant for PureTech Health.