Ingestion of potassium iodide (KI) offers effective protection against irradiation of the thyroid after accidental exposure to radioactive iodine. This prophylaxis aims at rapidly obtaining maximal thyroid protection without adverse effects. This article reviews studies on iodine kinetics in humans and on the efficacy of KI in protecting the thyroid. In adults with normal thyroid function, ingestion of 100 mg of iodide just before exposure to radioactive iodine blocks at least 95% of the thyroid dose. If exposure persists after iodide ingestion (100 mg), the percentage of averted dose may decrease significantly. Daily ingestion of a dose of 15 mg of KI would then maintain the thyroid blockade at a level above 90%. The efficacy of iodide and the occurrence of antithyroid effects also depend on external and individual factors such as dietary iodine intake, thyroid function, and age. The KI dosage regimen should be adjusted for age at exposure. For the fetus, the newborn, children, and adolescents, the risk of radiation-induced thyroid cancer in case of accidental exposure to radioactive iodine justifies KI prophylaxis, despite the risk of hypothyroidism, especially in newborns. For the elderly, the benefits of KI may be lower than the risk of iodine-induced hyperthyroidism.