The presence of RNAs in the extracellular milieu has sparked the hypothesis that RNA may play a role in mammalian cell–cell communication. As functional nucleic acids transfer from cell to cell in plants and nematodes, the idea that mammalian cells also transfer functional extracellular RNA (exRNA) is enticing. However, untangling the role of mammalian exRNAs poses considerable experimental challenges. This Review discusses the evidence for and against functional exRNAs in mammals and their proposed roles in health and disease, such as cancer and cardiovascular disease. We conclude with a discussion of the forward-looking prospects for studying the potential of mammalian exRNAs as mediators of cell–cell communication.