Spa therapy in Misasa (Tottori Prefecture, Japan) is renowned worldwide for its radon therapy (particularly high-concentration radon hot-air bath therapy) along with mine therapy in Bad Gastein (Austria) and Montana (USA). Radon therapy is indicated for diseases related to the respiratory system, pain, digestive disorders, chronic degeneration, and aging caused by reactive oxygen species; however, most of these indications are based on empirical prescriptions. To address this, the authors have been conducting basic research to experimentally and mathematically identify significant radon and its progeny exposure pathways and their related behaviors in the body. The aim is to quantitatively evaluate the relationship between the biological reactions caused by radon inhalation and the absorbed doses in tissues and organs, and to elucidate new mechanisms related to these indications. Therefore, the mechanisms are being elucidated in terms of a series of moderate physiological stimuli caused by small amounts of oxidative stress induced by radon inhalation. Specifically, radon inhalation enhances antioxidant, immune regulation, and damage-repair functions; promotes anti-inflammation, hormone secretion, and circulatory metabolism; and induces apoptosis and heat shock proteins. New indications have been suggested, including inflammatory and neuropathic pain, inflammatory edema, gastric mucosal damage, ulcerative colitis, hyperuricemia, type 1 diabetes, liver and kidney damage, transient cerebral ischemia, and depression. Furthermore, combining radon therapy with antioxidants and therapeutic agents has been suggested to synergistically enhance the disease-suppressing effects of the therapy. Further clinical verification of the combined effects of radon therapy and conventional treatments is required to reduce the dosage of drugs that cause severe side effects.