The connections between neurons in the central nervous system are constantly changing in number and in strength. This process occurs through development and aging, but is also employed to enable learning and memory. Additionally, neurons must be able to constantly sense general activity patterns and make slow adjustments in a homeostatic manner in order for inputs to remain meaningful. One of the ways in which neurons can manage the control of their connections is through manipulations of proteins at synapses. This can be accomplished through control of protein synthesis, trafficking, and degradation. Glutamate receptors such as AMPA receptors as well as a number of postsynaptic scaffolding proteins are subject to a variety of posttranslational modifications and can be synthesized and degraded in an activity-dependent manner. Recently, it has become clear that multiple steps in degradation pathways can be affected by changes in synaptic activity, and that this regulation can have an immense impact on synaptic strength. However, the exact mechanisms through which degradation systems are regulated has largely remained a mystery. Here, we explore the regulation both of ubiquitination and proteasome-dependent degradation, uncovering novel ways in which synaptic activity interacts with these systems. First, we demonstrate that the activity-dependent ubiquitination of surface AMPA receptors is accomplished through synaptic recruitment of the ubiquitin ligase Nedd4-1, and show that this ligase is critical in homeostatic downscaling of synaptic strength. Additionally, we unveil a role for this ligase in the synaptic depression observed in models of Alzheimer’s disease, illustrating that regulation of Nedd4-1 can go awry. Next, we demonstrate that control of excitatory synapses can also be accomplished with the conjugation of the small ubiquitin-like molecule NEDD8, known to regulate the activity of a number of ubiquitin ligases. Finally, we explore the role of CaMKII-dependent phosphorylation of the Rpt6 subunit of 26S proteasomes in plasticity and learning. These studies add to our knowledge of how protein degradation can be regulated by activity and how this regulation can impact synaptic plasticity.