The ubiquitin-proteasome system (UPS) is a ubiquitous, major pathway of protein degradation that is involved in most cellular processes by regulating the abundance of certain proteins. Accumulating evidence indicates a role for the UPS in specific functions of neurons. In this chapter, we first introduce the role of the UPS in neuronal function and the mechanism of UPS regulation following synaptic activity. Then, we focus on the recently revealed, distinct role of the UPS in the destabilization of a reactivated memory. Finally, we discuss the physiological role of this destabilization process. The reactivated memory may undergo modification from the initial memory depending on the context in which the memory is reactivated, which we will term memory reorganization. We will introduce the role of the protein degradation-dependent destabilization process for memory reorganization and suggest a hypothetical model combining the recent findings.