Proteolysis is an irreversible physiological process that can result in the termination or activation of protein function. Many transmembrane proteins that are involved in the cellular communication between immune cells and structural cells — for example, Notch, CD23, CD44, and membrane-anchored cytokines and their receptors — are cleaved by the ADAM (a disintegrin and metalloproteinase) family of enzymes. Here, we review recent insights into the molecular activation, substrate specificity and function of ADAM proteins in the development and regulation of the immune system, with a particular focus on the roles of ADAM10 and ADAM17.