Hypoxic-ischemic brain damage remains an outstanding cause of death and long-lasting disabilities for newborns worldwide. Among the different constituents of the complex cascade of events leading to neuronal death after a hypoxic-ischemic insult in immature brain, nitric oxide (NO) plays a role of great importance. The evidence suggests that NO can exert both protective and deleterious effects depending on factors such as the NOS isoform and the temporal stage after the onset of the ischemic brain injury. Immediately after brain hypoxic-ischemic insult, NO release from eNOS is protective mainly by promoting vasodilation; in this regard, NO is to be of particular relevance for autoregulatory responses of newborn cerebral vessels. However, subsequent NO production by overactivation of nNOS and, later, NO release by de novo expression of iNOS contributes to the brain damage; immature brain is particularly sensitive to this circumstance, as iNOS is more easily and more intensively expressed in newborns after hypoxic-ischemic insults, and newborns have less antioxidant activity, as compared with adults. Thus, NOS emerges as a decisive target for neuroprotection after newborn asphyxia. Toxic effects of drugs specifically acting on NOS, however, still prevent their use in humans. Nevertheless, recent evidences on the unspecific modulatory effect on NOS of substances as erythropoietin or cannabinoids, with few known adverse effects in newborns, offer promising perspectives.