The brain changes in response to experience and altered environment. This neural plasticity is largely mediated by morphological and functional modification of synapses, a process that depends on both synthesis and degradation of proteins. It is now clear that regulated proteolysis plays a critical role in the remodeling of synapses, learning and memory, and neurodevelopment. Here, we highlight the mechanisms and functions of proteolysis in synaptic plasticity and discuss its alteration in disease states.