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Migraine is a complex neurological disorder with immense socioeconomic impact, yet it remains under-recognized and under-treated. Recent advances highlight migraine as a multifactorial disease shaped by genetic susceptibility and environmental influences. Genome-wide association studies, including ours, have identified over 100 genetic risk loci affecting neuronal and vascular functions, but genetics alone cannot explain migraine occurrence. Factors contributing to allostatic load—both intrinsic and environmental—may alter brain excitability and attack thresholds. Notably, integrating genetic data with migraine-associated microRNA levels in our study achieved nearly 90% predictive accuracy for diagnosis. Among various mechanisms, neuroinflammation has emerged as a pivotal yet incompletely understood factor. Our recent work demonstrates that neuronal activation of the NLRP3 inflammasome, downstream of the P2X7–Panx1 complex, mediates cortical spreading depolarization (CSD)-induced neuroinflammatory cascades. This process amplifies glial activation, promotes cortical inflammation, and triggers trigeminovascular activation leading to headache. Clinically, we observed impaired glymphatic and meningeal lymphatic transport in migraine, particularly chronic migraine. Our preliminary preclinical findings further reveal that while CSD induces transient perivascular cerebrospinal fluid influx and immediate trigeminal activation, it subsequently causes lasting dysfunction in glymphatic and meningeal lymphatic drainage. This impairment likely hinders clearance of inflammatory mediators, perpetuating neuroinflammation and pain. These findings highlight a mechanistic link between cortical neuroinflammation, impaired brain waste clearance, and trigeminovascular activation in migraine. Ongoing research aims to elucidate the molecular and circuit-level underpinnings of this interplay, which may provide a novel direction for developing migraine therapeutics.