Originally discovered because of its role in the regulation of glucose metabolism, GSK-3 is now widely recognized as a crucial player in many cellular functions. Control of GSK-3 activity occurs by complex mechanisms that are each dependent upon specific signaling pathways. Furthermore, GSK-3 dysfunction has been linked to a number of pathologies, including Alzheimer's disease (AD). In particular, the involvement of GSK-3 in several key pathophysiological pathways leading to AD and neurodegenerative diseases has placed this enzyme in a central position in this disorder. In this article, the authors will specifically focus on the role of this enzyme as a key regulator of synaptic plasticity and how alterations in the GSK-3 synaptic functions may be a major factor in AD and other neurodegenerative disorders.