Changes in synaptic function require both qualitative and quantitative reorganization of the synaptic components. Ca2+ plays a central role in this process, but the mechanism has not been fully elucidated. Zhang et al report a novel mechanism whereby Ca2+/calmodulin (CaM) regulates the stability of the postsynaptic scaffold. Ca2+/CaM interacts with PSD-95, a core protein in the postsynaptic density (PSD) that supports synaptic signaling and structural components. Ca2+/CaM interferes with the palmitoylation of PSD-95, resulting in the dissociation of PSD-95 from the postsynaptic membrane. This process may explain the reduction of surface glutamate receptor observed during synaptic depression and homeostatic regulation of the synaptic response after prolonged neuronal activity.