Dynamic changes in the structure and function of synapses in response to the environment, termed synaptic plasticity, are the cellular basis of learning and memory. At excitatory synapses, activation of NMDA receptors by glutamate leads to calcium influx triggering intracellular pathways that promote the trafficking of AMPA receptors to the post-synaptic membrane and actin remodeling. New evidence shows that Wnt secreted proteins, known for their role in synapse development, are essential for early stages of long-term potentiation, a form of plasticity that increases synaptic strength. Here, we review recent progress in this area and the significance of Wnt signaling to synaptic plasticity in health and disease.