In vitro studies have shown that monosialoganglioside GM1 reduces excitatory amino acid-related neurotoxicity by limiting the downstream consequences of abusive excitatory amino acid receptor stimulation, while enhancing neuronotrophic factor action in a variety of neuronal cell types. Systemic administration of GM1 appears to be efficacious in reducing acute nerve cell damage and in facilitating medium- and long-term functional recovery after brain injury. Although the mechanism of action remains unclear, it appears likely that GM1 protective effects in the acute injury phase are at least in part due to the attenuation of excitotoxicity, while the long-term functional recovery might reflect GM1 potentiation of neuronotrophic factors. The potential therapeutic efficacy of GM1 administration in different conditions in humans, as suggested by pioneer clinical studies, is reviewed. Further larger, randomized, double-blind clinical studies are necessary to define the therapeutic efficacy.