Integrins are large, membrane-spanning, heterodimeric proteins essential for metazoan existence. They consist of α and β subunits, with the head containing ligand binding sites and subunit association. The receptor dimer is mostly extracellular, but both subunits traverse the plasma membrane. Integrins have evolved a highly responsive activation mechanism regulated by changes in tertiary and quaternary structure. This review summarizes recent progress in the structural and molecular functional studies of integrins, including the structure of intact ectodomains, membrane spanning regions, cytoplasmic tails, and ligand binding. The α and β subunits have flexible linkers and contain several domains. The ectodomains of integrins are known to adopt a "bent" conformation, with the ligand binding site near the membrane surface. Recent crystal structures of αVβ3, αIIbβ3, and αxβ2 have provided insights into the overall topology and structure of integrin ectodomains. The α-subunit consists of four or five extracellular domains, including a β-propeller, a thigh, and two calf domains. The β-subunit has seven domains with flexible interconnections, including a β-I domain inserted into a hybrid domain. Cation binding sites, such as the MIDAS and SyMBS sites, are crucial for ligand binding and activation. The membrane spanning helices of the α and β subunits form an inactive resting receptor, and their association results in an extended conformation. The cytoplasmic tails of integrins can form transient interactions with various proteins, such as talin and kindlin, which are important for activation. Structural studies of intact integrins using techniques like cryoelectron tomography and FRET have provided insights into the activation process, with evidence supporting the "switchblade" model of conformational change. Integrin-ligand interactions are regulated by conformational changes, and activating mAbs often recognize epitopes in the β subunit, suggesting a large-scale alteration in the conformation of the whole integrin. The process of integrin activation involves clustering and conformational changes, with the β-I domain and hybrid domain playing central roles. Integrin antagonists, such as peptidomimetic inhibitors and monoclonal antibodies, have been developed as therapeutic agents, and their mechanisms of action are increasingly understood. Despite significant progress, several questions remain, including the outside-in signaling pathway and the process of inactivation.Integrins are large, membrane-spanning, heterodimeric proteins essential for metazoan existence. They consist of α and β subunits, with the head containing ligand binding sites and subunit association. The receptor dimer is mostly extracellular, but both subunits traverse the plasma membrane. Integrins have evolved a highly responsive activation mechanism regulated by changes in tertiary and quaternary structure. This review summarizes recent progress in the structural and molecular functional studies of integrins, including the structure of intact ectodomains, membrane spanning regions, cytoplasmic tails, and ligand binding. The α and β subunits have flexible linkers and contain several domains. The ectodomains of integrins are known to adopt a "bent" conformation, with the ligand binding site near the membrane surface. Recent crystal structures of αVβ3, αIIbβ3, and αxβ2 have provided insights into the overall topology and structure of integrin ectodomains. The α-subunit consists of four or five extracellular domains, including a β-propeller, a thigh, and two calf domains. The β-subunit has seven domains with flexible interconnections, including a β-I domain inserted into a hybrid domain. Cation binding sites, such as the MIDAS and SyMBS sites, are crucial for ligand binding and activation. The membrane spanning helices of the α and β subunits form an inactive resting receptor, and their association results in an extended conformation. The cytoplasmic tails of integrins can form transient interactions with various proteins, such as talin and kindlin, which are important for activation. Structural studies of intact integrins using techniques like cryoelectron tomography and FRET have provided insights into the activation process, with evidence supporting the "switchblade" model of conformational change. Integrin-ligand interactions are regulated by conformational changes, and activating mAbs often recognize epitopes in the β subunit, suggesting a large-scale alteration in the conformation of the whole integrin. The process of integrin activation involves clustering and conformational changes, with the β-I domain and hybrid domain playing central roles. Integrin antagonists, such as peptidomimetic inhibitors and monoclonal antibodies, have been developed as therapeutic agents, and their mechanisms of action are increasingly understood. Despite significant progress, several questions remain, including the outside-in signaling pathway and the process of inactivation.