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Exosomes are small, cell-released vesicles (40–100 nm in size) with the potential to transfer proteins, lipids, small RNAs, messenger RNAs, or DNA between cells via interstitial fluids. Due to their role in tissue homeostasis, exosomes have emerged as a new type of therapeutic and diagnostic (theranostic) tool in the noninvasive assessment of organ response to injury or treatment and in the development of reliable organ-protective intensive therapy. Our review provides current insights into the role of exosomes in the personalized management of injury and repair responses in critical illness.Data were obtained from a PubMed search of the most recent medical literature, including the PubMed “related articles” search methodology.Articles considered include original articles, review articles and conference proceedings.A detailed review of scientific, peer-reviewed data was performed. Relevant pre-clinical and clinical studies were included and summarized.Current scientific evidence is focused on the following: 1) Frontiers in the management of critical illness; 2) Biogenesis, characterization, and function of circulating exosomes; 3) The role of exosomes in acute lung injury; 4) The role of exosomes in acute cardiac injury; 5) The role of exosomes in acute kidney injury; 6) The role of exosomes in sepsis; 7) Limitations of exosome isolation protocols; and 8) Perspectives in the theranostic use of exosomes.Circulating levels of exosomes are associated with the onset and clinical course of critical illness. Exosomes released from cells with different phenotypes exert different functions in order to protect tissue and preserve organ function. Therefore, multifunctional exosomes with combined diagnostic and therapeutic functions show great promise in terms of personalized nanomedicine for patient-specific diagnosis and treatment of critical illness.