Antioxidants are known to prevent oxidative damage in cells caused by radiation. We have previously reported that whole-body irradiation with low doses of gamma rays to mice elevates the antioxidant thioredoxin-1 (Trx-1) levels in several organs. Furthermore, gamma ray irradiation also causes ATP release from the exposed cells. Extracellular ATP release in response to various stimuli has been reported to regulate the expression of intracellular antioxidants through activation of purinergic P2 receptors.Here, we review the relation between gamma-radiation-induced ATP release and the induction of cellular Trx-1 via purinergic signaling. Irradiation with gamma rays or exogenously adding ATP cause an increase in Trx-1 expression, and these phenomena disappear in the presence of an ecto-nucleotidase. Further, it is revealed that ATP generates intracellular reactive oxygen species (ROS), and thereby increases Trx-1 expression as an adaptive response to ROS.These findings suggest that gamma-radiation-induced release of extracellular ATP may contribute to the production of ROS via purinergic signaling, thereby leading to the promotion of intracellular antioxidants in response to an oxidative stress.