Various surface molecules undergo regulated cleavage by the disintegrin and metalloproteinases ADAM10 and ADAM17. The list of substrates includes molecules involved in brain pathology, inflammation and cancer. In the brain both proteases mediate neuroprotective cleavage events such as inactivation of amyloid precursor protein. In inflammatory settings signaling of cytokines including TNFα and IL-6 is triggered by proteolytic release of soluble agonists and leukocyte recruitment is controlled by the cleavage of adhesion molecules. Moreover, in tumors, ADAM10- and ADAM17-mediated shedding events trigger proliferative signaling via activation of growth factors including ErbB family members. Concepts of either increasing ADAM10- or ADAM17-activity to limit neurodegeneration or suppressing their activity to block inflammation or tumor growth have to be carefully scrutinized for their potential side effects in various tissues and pathologies.