The activity of a cell surface protease, particularly an ADAM, is determined in a rapid and sensitive assay employing a whole cell system. The assays are effective to identify effector molecules that affect the activity of a cell surface protease directly or indirectly, and to screen for therapeutic agents that modulate those effector molecules. The assays can also be used to screen for therapeutic agents that modulate the activity of a cell surface protease associated with a disease or medical condition. Kits comprising at least one component of the present assays are also provided.