Many life-essential molecules such as growth factors, cytokines, ectoenzymes, and decoy receptors are produced by ectodomain cleavage of transmembrane precursor molecules. Not surprisingly, misregulation of such essential functions is linked to numerous diseases. Ectodomain cleavage is the function of transmembrane ADAMs (a disintegrin and metalloprotease) and other membrane-bound metalloproteases, which have an extracellular catalytic domain. Almost all work on ectodomain cleavage regulation has focused on the control of enzyme activity determined by substrate cleavage as surrogate. However, the number of substrates far exceeds the number of enzymes. Specificity can therefore not be achieved by solely modulating enzyme activity. Here, we argue that specific regulatory pathways must exist to control the availability and susceptibility of substrates.