Integrins are α/β heterodimeric, type I transmembrane proteins that mediate cell-to-cell and cell-to-extracellular matrix interactions. A hallmark of integrins is that ligand binding requires an activation step that is associated with profound conformational changes that affect the entire molecule including the separation of the α/β transmembrane domains (TMDs). We discovered that the α/β-integrin TMDs have an additional key function: the TMD clasp in the endoplasmic reticulum acts as an allosteric activator assisting the distant α/β-ectodomain head association and folding. I will discuss how we discovered this essential integrin TMD function and how it links to disease.