Integrins are cell adhesion molecules that mediate interactions between cells, cells and the extracellular matrix, and cells and pathogens. They play critical roles in the immune system, including leukocyte trafficking, migration, immunological synapse formation, costimulation, and phagocytosis. Integrin adhesiveness can be dynamically regulated through inside-out signaling, and ligand binding transmits signals from the extracellular domain to the cytoplasm in the outside-in direction. Structural, biochemical, and biophysical studies have advanced understanding of integrin bidirectional signaling across the plasma membrane. Large-scale reorientations of the ectodomain can couple to conformational changes in ligand-binding sites and are linked to changes in α and β subunit transmembrane domain association. This review focuses on integrin structure in relation to affinity modulation, ligand binding, outside-in signaling, and cell surface distribution dynamics. The α I domain is a key region in integrins, containing about 200 amino acids and serving as a paradigm for understanding conformational regulation and ligand binding. The α I domain adopts a dinucleotide-binding or Rossmann fold, with α-helices surrounding a central β-sheet. The domain has a divalent cation-binding site that physiologically binds Mg²⁺, and the bound Mg²⁺ is ligated by five side chains located in three different loops. The α I domain has three distinct conformations: closed, intermediate, and open. These conformations demonstrate distinct coordination of the metal in the MIDAS, arrangement of the β6-α7 loop, and axial disposition of the C-terminal α7-helix along the side of the I domain. The closed conformation is the low-energy conformation, while the open conformation is stabilized by interactions with other integrin domains. The α I domain can be modulated by ligand binding, which induces conformational changes and increases affinity for ligands. The α I domain has a metal ion-dependent adhesion site (MIDAS) that is essential for ligand binding. The MIDAS is a site where metal-coordinating residues and residues surrounding the metal-binding site are important for ligand binding. The α I domain can be modulated by small molecule allosteric inhibitors that bind underneath the C-terminal α-helix of the αL I domain. These inhibitors stabilize the closed conformation of the I domain by preventing downward axial shift of the α7-helix and thereby preventing MIDAS rearrangements necessary for efficient ligand binding. Ligand recognition by α I domains has been elucidated by crystal structures of the α2 I domain in complex with a triple-helical collagenous peptide and the αL I domain in complex with ICAM-1 and ICAM-3. ICAM-1, -2, -3, -4, and -5 are cell surface molecules with 2 to 9 IgSFIntegrins are cell adhesion molecules that mediate interactions between cells, cells and the extracellular matrix, and cells and pathogens. They play critical roles in the immune system, including leukocyte trafficking, migration, immunological synapse formation, costimulation, and phagocytosis. Integrin adhesiveness can be dynamically regulated through inside-out signaling, and ligand binding transmits signals from the extracellular domain to the cytoplasm in the outside-in direction. Structural, biochemical, and biophysical studies have advanced understanding of integrin bidirectional signaling across the plasma membrane. Large-scale reorientations of the ectodomain can couple to conformational changes in ligand-binding sites and are linked to changes in α and β subunit transmembrane domain association. This review focuses on integrin structure in relation to affinity modulation, ligand binding, outside-in signaling, and cell surface distribution dynamics. The α I domain is a key region in integrins, containing about 200 amino acids and serving as a paradigm for understanding conformational regulation and ligand binding. The α I domain adopts a dinucleotide-binding or Rossmann fold, with α-helices surrounding a central β-sheet. The domain has a divalent cation-binding site that physiologically binds Mg²⁺, and the bound Mg²⁺ is ligated by five side chains located in three different loops. The α I domain has three distinct conformations: closed, intermediate, and open. These conformations demonstrate distinct coordination of the metal in the MIDAS, arrangement of the β6-α7 loop, and axial disposition of the C-terminal α7-helix along the side of the I domain. The closed conformation is the low-energy conformation, while the open conformation is stabilized by interactions with other integrin domains. The α I domain can be modulated by ligand binding, which induces conformational changes and increases affinity for ligands. The α I domain has a metal ion-dependent adhesion site (MIDAS) that is essential for ligand binding. The MIDAS is a site where metal-coordinating residues and residues surrounding the metal-binding site are important for ligand binding. The α I domain can be modulated by small molecule allosteric inhibitors that bind underneath the C-terminal α-helix of the αL I domain. These inhibitors stabilize the closed conformation of the I domain by preventing downward axial shift of the α7-helix and thereby preventing MIDAS rearrangements necessary for efficient ligand binding. Ligand recognition by α I domains has been elucidated by crystal structures of the α2 I domain in complex with a triple-helical collagenous peptide and the αL I domain in complex with ICAM-1 and ICAM-3. ICAM-1, -2, -3, -4, and -5 are cell surface molecules with 2 to 9 IgSF