Fasting or skipping meals are well-characterized migraine triggers. However, mechanisms of the fasting-induced migraine headache are unclear. Here, we review the recent developments on brain glycogen metabolism and its modulation by sympathetic activity and propose that insufficient supply of glycogen-derived glucose at the onset of intense synaptic activity may lead to an imbalance between the excitatory and inhibitory terminals, causing collective depolarization of neurons and astrocytes in a network. This may activate perivascular trigeminal afferents by opening neuronal pannexin1 channels and initiating parenchymal inflammatory pathways. Depending on whether or not network depolarization spreads or remains local, fasting may trigger migraine headache with or without aura.