Dysregulation of intracellular calcium homeostasis is a common hallmark of degenerating neurons, at some point in the cell death cascade. It is also a feature of many neurological disorders, including stroke, epilepsy, trauma and several neurodegenerative diseases, commonly associated with the phenomenon of excitotoxicity. Nitric oxide (NO) is a signaling gaseous molecule formed in the brain as a part of the normal intracellular calcium signalling, playing highly diversified roles in cellular physiology. For the past 20 years, numerous studies have demonstrated that NO can acts as a neurotoxin in several disorders of the nervous system. More recent evidence shows that NO can also act as a neuroprotective agent. Calcium-dependent proteases, like calpains, were also shown to be activated in several conditions of the nervous system that involve excitotoxic neurodegeneration, and have been receiving increasing attention as therapeutical targets in recent years. In this review, we bring together the recent literature concerning the involvement of NO and calpains in neuronal survival and death. The biological pathways involved with NO and calpains may be good drug targets to alter neurodegenerative diseases.