Background: Cortical spreading depression (SD) is thought to underlie migraine aura but mechanisms of triggering SD in the structurally normal, well-nourished cortex of migraine patients remain unknown. Synaptic and network dysfunctions appear to underlie episodic neurological disorders, including migraine. The narrative review summarizes old and recent experimental evidence for triggering SD by synaptic/network mechanisms and discusses the relevance of the data to migraine pathogenesis. Our hypothesis is that under some conditions synaptic/network hyperactivity may reliably ignite SD, and this mechanism may underlie triggering migraine aura in patients. Findings: High-frequency tetanic stimulation of the cortex reliably triggers SD in synaptically connected regions; SD is a reliable cortical response to acute hyperexcitability (epileptic seizures), though chronic epilepsy prevents triggering SD; in the hyperexcitable cortex, SD may be triggered by sensory stimulation; compromised glutamatergic transmission plays the critical role in triggering SD. Conclusion: SD may be triggered by dynamic network instability produced by dysfunction of calcium-dependent glutamate release. Synaptic drive from subcortical sensory processing structures (brainstem and/or thalamocortical networks) is able to evoke depolarization of hyperexcitable cortical neurons sufficient to initiate the regenerative SD process. Studying SD initiation by synaptic/network hyperexcitability may provide insights into basic mechanisms underlying SD generation in migraine brain.