The nature of TSH-receptor interaction has been evaluated using whole thyroid cells, lymphocytes in continuous culture and thyroid membrane preparations. We have characterized two different TSH binding sites with different specificities and affinities. Only the high affinity site shows binding characteristics consistent with the receptor that mediates the biologic action of TSH. The latter site has been used to characterize the TSH receptor-binding activity of pituitary and placental glycoprotein hormones as well as immunoglobulins present in patients with various disorders of thyroid function.