The article reviews the final steps of integrin activation, focusing on the 'end game' of this process. Integrins, heterodimeric transmembrane receptors, play crucial roles in cell adhesion, migration, and other cellular processes. The activation of integrins involves triggering events, intermediate signaling events, and the interaction of integrins with cytoplasmic regulators, which changes their affinity for ligands. Recent studies have provided insights into the structure of integrin transmembrane domains and how the final steps of activation are mediated by proteins like talins and kindlins. The article discusses the structural elements of integrin transmembrane domains, the role of cytoplasmic domains in activation, and the importance of talins and kindlins in activating integrins. It also explores the potential for negative regulators of integrin activation and the possibility of activating integrins from the outside. The review highlights the significance of these findings for therapeutic strategies targeting integrin activation in diseases such as atherothrombosis and cancer.The article reviews the final steps of integrin activation, focusing on the 'end game' of this process. Integrins, heterodimeric transmembrane receptors, play crucial roles in cell adhesion, migration, and other cellular processes. The activation of integrins involves triggering events, intermediate signaling events, and the interaction of integrins with cytoplasmic regulators, which changes their affinity for ligands. Recent studies have provided insights into the structure of integrin transmembrane domains and how the final steps of activation are mediated by proteins like talins and kindlins. The article discusses the structural elements of integrin transmembrane domains, the role of cytoplasmic domains in activation, and the importance of talins and kindlins in activating integrins. It also explores the potential for negative regulators of integrin activation and the possibility of activating integrins from the outside. The review highlights the significance of these findings for therapeutic strategies targeting integrin activation in diseases such as atherothrombosis and cancer.