Integrins, the major cell surface receptors mediating cell–extracellular matrix (ECM) adhesion, are central to the basic physiology underlying all multicellular organisms. As the complexity of animal body architecture increased, integrins were forced to acquire recognition capabilities toward the wide variety of ECM ligands and cell surface counter-receptors that emerged during evolution. Structural determination of the integrin–ligand complexes for both I domain-containing and non-I domain-containing integrins revealed two fundamentally different types of integrin-binding surfaces. In addition, recent advances in the biochemical and pharmacological characterization of the integrin–ligand interactions are beginning to reveal how integrins achieve specific recognition of wide variety of ligands using a small binding cleft at the subunit interface common to all integrins.