A human glucagon receptor has been cloned from human liver tissue. The 1578-bp cDNA clone encodes a protein of 477 amino acids with 82% identity to the rat glucagon receptor. The predicted secondary structure and homology to known proteins places this receptor within the superfamily of seven transmembrane domain G protein coupled receptors. Transfection of the human glucagon receptor into COS-7 cells confers upon them high affinity binding for [125I] glucagon. In membranes prepared from COS-7 cells transfected with the human glucagon receptor, the binding of [125I] glucagon is inhibited with the rank order of potency glucagon > oxyntomodulin > glucagon-like peptide 1 (7-36) amide > glucagon-like peptide 2 = gastric inhibitory peptide = secretin.