Domoic acid (DA), an agonist of non-N-methyl-D-aspartate (non-NMDA) receptor subtype including kainate receptor, was identified as a potent neurotoxin showing involvement in neuropathological processes like neuronal degeneration and atrophy. In the past decade evidence indicating a role for excitatory amino acids in association with neurological disorders has been accumulating. Although the mechanisms underlying the neuronal damage induced by DA are not yet fully understood, many intracellular processes are thought to contribute towards DA-induced excitotoxic injury, acting in combination leading to cell death. In this review article, we report the leading hypotheses in the understanding of DA-induced neurotoxicity, which focus on the role of DA in neuropathological manifestations, the formation of the retrograde messenger molecule nitric oxide (NO) for the production of free radicals in the development of neuronal damage, the activation of glial cells (microglia and astrocytes) in response to DA-induced neuronal damage and the neuroprotective role of melatonin as a free radical scavenger or antioxidant in DA-induced neurotoxicity. The possible implications of molecular mechanism underlying the neurotoxicity in association with necrosis, apoptosis, nitric oxide synthases (nNos and iNOS) and glutamate receptors (NMDAR1 and GluR2) related genes and their expression in DA-induced neuronal damage in the hippocampus have been discussed.