Exosomes are tiny vesicles secreted by the vast majority of cells and play an important role in physiological as well as pathological processes in the body. Circulating exosomes in Lung Transplant Recipients (LTxR) undergoing rejection contain mismatched Human Leukocyte Antigens (HLA) and lung-associated autoantigens (e.g., K-alpha1 microtubule protein and collagen V), which may induce autoantibodies, and the circulating exosomes trigger an immune response that results in rejection of the lung transplant recipient. This article discusses the role of exosomes in lung transplantation from three perspectives: exosomes as a biomarker for rejection after lung transplantation; the mechanism of exosome-mediated activation of the immune response; and the potential of exosomes as a therapeutic strategy.