Several lines of evidence suggest a role for oxidative cascades of events leading to neurodegeneration associated with Parkinsons, Alzheimer, Huntington diseases, and amyotrophic lateral sclerosis. In agreement with the notion of oxidative/nitrosative involvement in these chronic diseases, in vivo models of disease as well as biochemical and epidemiological evidence suggest a neuroprotective role for natural antioxidant polyphenols in neurodegenerative diseases. However, the molecular mechanisms for neuroprotection do not merely rely on a direct radical scavenging/antioxidant activity. Rather, polyphenols may function at several cellular levels, including direct interaction and modulation of enzymatic activities and the regulation of signaling pathways with implications for cell survival and death. Nitric oxide is a paradigmatic example. In view of the wide collection of activities of nitric oxide in the brain, ranging from synaptic plasticity to excitotoxicity, the regulation of its rate and pattern of production and decay in tissues by polyphenols is of obvious physiological relevance. Thus, the elucidation of polyphenol activities at the molecular level may lay the foundations for new pharmacological approaches in relation to neurodegeneration. In this review, the molecular mechanisms underlying the potential health promoting effects of natural polyphenols in connection with neurodegenerative diseases are discussed. Additionally, we provide evidence for a modulatory effect of hydroxycinnamic phenol caffeic acid on glutamate NMDA receptor/nitric oxide pathway in hippocampal slices.