Alzheimer's disease (AD), the most common neurodegenerative disease in the elderly population, is characterized by the hippocampal deposition of fibrils formed by amyloid β-protein (Aβ), a 40- to 42-amino-acid peptide. The folding of Aβ into neurotoxic oligomeric, protofibrillar, and fibrillar assemblies is believed to mediate the key pathologic event in AD. The hippocampus is especially susceptible in AD and early degenerative symptoms include significant deficits in the performance of hippocampal-dependent cognitive abilities such as spatial learning and memory. Transgenic mouse models of AD that express C-terminal segments or mutant variants of amyloid precursor protein, the protein from which Aβ is derived, exhibit age-dependent spatial memory impairment and attenuated long-term potentiation (LTP) in the hippocampal CA1 and dentate gyrus (DG) regions. Recent experimental evidence suggests that Aβ disturbsN-methyl-D-aspartic acid (NMDA) receptor-dependent LTP induction in the CA1 and DG both in vivo and in vitro. Furthermore, these studies suggest that Aβ specifically interferes with several major signaling pathways downstream of the NMDA receptor, including the Ca2+-dependent protein phosphatase calcineurin, Ca2+/calmodulin-dependent protein kinase II (CaMKII), protein phosphatase 1, and cAMP response element-binding protein (CREB). The influence of Aβ on each of these downstream effectors of the NMDA receptor is reviewed in this article. Additionally, other mechanisms of LTP modulation, such as Aβ attenuation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor currents, are briefly discussed.