Wnt signaling pathways play important roles in various developmental and oncogenic processes. In the nervous system, Wnt signaling regulates neuronal morphogenesis and synaptic differentiation. Disturbance of Wnt signaling is implicated in the pathogenesis of neurological diseases. Recent studies indicate that Wnt signaling in neurons is closely coupled to synaptic activation, and that the activity-regulated Wnt signaling is critical for the expression of synaptic plasticity and the formation of memory. Dysregulation of the activity-regulated Wnt signaling may have a significant impact on the function of the nervous system. In this article, we will review the identified mechanisms by which synaptic activity controls Wnt signaling in neurons and the neurological functions of the activity-regulated Wnt signaling under normal and specific disease conditions. In particular, we will discuss the role of Wnt signaling in the pathogenesis of chronic pain.