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Radiotherapy is one of the most effective treatment methods for various solid tumors. Bidirectional signal transduction between cancer cells and stromal cells within the irradiated microenvironment is important in cancer development and treatment responsiveness. Exosomes, initially considered as “garbage bins” for unwanted from cells, are now understood to perform a variety of functions in interactions within the tumor microenvironment. Exosome-mediated regulation processes are rebuilt under the irradiation stimuli, because the exosome production, uptake, and contents are markedly modified by irradiation. In turn, irradiation-modified exosomes may modulate the cell response to irradiation through feedback regulation. Here, we review current knowledge and discuss the roles of exosome-mediated interactions between cells under radiotherapy conditions.