There is considerable evidence for elimination of synapses and loss of neurons during development of the nervous system. Electrical activity in developing neural circuits induces functional and structural refinement of many synaptic connections, but it is unclear whether the fundamental mechanism is one of strengthening appropriate synapses, combined with the regression of synapses that fail to become adequately stabilized, versus a mechanism of elimination that specifically acts on inappropriate connections. A model of selective synapse elimination, based on the activity-dependent release of proteases and glial-derived protease inhibitors, is presented and supported by evidence from an in vitro preparation of the mouse neuromuscular junction.