The insulin and IGF-1 receptors are members of the superfamily of receptor tyrosine kinases (RTKs). Many of these have been implicated in human cancers due to amplification, overexpression or somatic mutations of the gene. Congenital mutations of the RTKs are implicated in a growing number of inherited syndromes. Unlike most RTKs that are single-chain monomeric transmembrane polypeptides, the insulin and IGF-1 receptors are dimers made of two extracellular alpha subunits and two transmembrane beta subunits containing the tyrosine kinase domain. The alpha subunits contain the ligand binding sites, of which at least three subdomains have been mapped by photoaffinity cross-linking, alanine-scanning mutagenesis or minimized receptor constructs. All RTKs are dimeric or oligomeric in the ligand-activated form, a mechanism that allows for transphosphorylation of the kinase domains and triggers the signalling cascade. The residues of insulin involved in receptor binding have been mapped by alanine-scanning mutagenesis. They form at least two major epitopes that partially overlap with the dimer- and hexamer-forming surfaces of the insulin molecule, and we propose that insulin is using those surfaces to cross-link the receptor alpha subunits. This mechanism provides a structural basis for negative cooperativity in binding, and probably also operates in the IGF-receptor interaction.