Glutamate is a key neurotransmitter in the central nervous system; however, excessive levels may produce neurotoxicity and the development of neurodegenerative diseases. Multiple mechanisms underlying glutamate-induced neurotoxicity have been discussed recently. Apoptosis is also a regulated process inherent to normal cellular brain development and/or maintenance. Nevertheless, a clear deregulation of the mitochondrial respiratory mechanism has been described in patients with neurodegeneration. Thus, a growing body of evidence suggests involvement of oxidative stress, inflammation, and apoptosis in neurodegenerative diseases. To highlight this, nitric oxide, an atypical neurotransmitter synthesized and released on demand by post-synaptic neurons, has many important implications for nerve cell survival and differentiation. Moreover, apoptosis induction or inhibition by nitric oxide may be explained by several mechanisms involving the expression/localization of the enzymatic precursors, bioavailability, and/or possible protein interaction. Consequently, synaptogenesis, synapse elimination, and neurotransmitter release are modulated by nitric oxide. Finally, of particular interest to current understanding, an emergent role of nitric oxide pathways has been discussed in relation to neurotoxicity from glutamate-induced apoptosis. These findings suggest that nitric oxide pathway modulation could prevent oxidative damage to neurons by apoptosis inhibition. This chapter discusses the emergent aspects of nitric oxide–mediated signaling in the brain, and how they can be related to neurotoxicity and the development of neurodegenerative diseases.