The thyroid-stimulating hormone (TSH, or thyrotropin) receptor (TSHR) mediates the activating action of TSH to the thyroid gland, resulting in the growth and proliferation of thyrocytes and thyroid hormone production. In Graves' disease, thyroid-stimulating autoantibodies can mimic TSH action and stimulate thyroid cells. This leads to hyperthyroidism and abnormal overproduction of thyroid hormone. TSHR-antibodies-binding epitopes on the receptor molecule are well studied. Mechanism of TSHR-autoantibodies production is more or less clear but a susceptibility gene, which is linked to their production, is still unknown. Genetic studies show no linkage between the TSHR gene and Graves' disease. Among three common polymorphisms in the TSHR gene, only the D727E germline polymorphism in the cytoplasmic tail of the receptor showed an association with the disease, and this association is weak. The absence of a strong genetic effect of the TSHR polymorphisms in such a common and complex disorder as Graves' disease may be explained by a high degree of evolutionary conservation in TSHR. This can be shown by naturally existing germline and somatic mutations in the TSHR gene that cause various types of nonautoimmune and hereditary thyroid disease.