The platelet integrin α_IIbβ₃ is required for platelet aggregation. Like other integrins, α_IIbβ₃ resides on cell surfaces in an equilibrium between inactive and active conformations. Recent experiments suggest that the shift between these conformations involves a global reorganization of the α_IIbβ₃ molecule and disruption of constraints imposed by the heteromeric association of the α_IIb and β₃ transmembrane and cytoplasmic domains. The biochemical, biophysical, and ultrastructural results that support this conclusion are discussed in this Review.