Genetic studies in familial hemiplegic migraine (FHM), a monogenic subtype of migraine with aura (MA), have led to the discovery of three genes: CACNA1A, ATP1A2, and SCN1A. Gene mutations seem to cause increased glutamate levels in the synaptic cleft that may facilitate cortical spreading depression (CSD), the hallmark of the migraine aura. There is no evidence, however, that these genes play an important role in common, complex (polygenic) migraine, although the pathophysiological mechanisms in both monogenic and complex migraine overlap as was shown by genome-wide association studies (GWAS) for complex migraine that demonstrated several genes with a role in glutamatergic neurotransmission.