The proteolytically functional ADAMs, of which there are 13 in the human, play key roles in the way that many different types of cells respond to their environment. They act as 'signalling scissors' within various membrane environments, including at the cell surface, orchestrating rapid changes in the status of their transmembrane protein substrates. The elucidation of the mode of regulation of these 'shedding' activities is consequently of pivotal importance in the understanding their roles, but is still rather understudied, with large gaps in our knowledge. This review will consider the major regulatory mechanisms that are known which indicate where further research is needed.