Background: The blood-brain barrier (BBB) is a highly specialized structure that maintains brain homeostasis by regulating molecular exchange between the bloodstream and the central nervous system. Ischemic stroke disrupts BBB integrity, leading to edema, neuroinflammation, and poor outcomes. Understanding the genetic regulation of BBB components is critical for developing targeted therapies. Methods: This narrative review synthesizes current literature on BBB structure, the neurovascular unit, and genetic mechanisms underlying BBB dysfunction in ischemic stroke. Key genes involved in tight junctions, inflammatory responses, matrix remodeling, and angiogenesis were analyzed, with a focus on CLDN5, MMP-9, VEGF, and IL-6. Evidence from animal models (e.g., MCAO, knockout mice) and human genetic studies was evaluated. Results: Key findings show that CLDN5 downregulation increases BBB permeability and edema. Elevated MMP-9 degrades tight junction proteins and extracellular matrix, contributing to hemorrhagic transformation. VEGF overexpression promotes angiogenesis but exacerbates BBB leakage and edema.  IL-6 drives neuroinflammation and correlates with worse stroke outcomes. Animal models confirm that knockout of MMP-9 or IL-6 reduces BBB disruption and infarct size, while CLDN5 knockout increases stroke susceptibility. Therapeutic perspectives include gene therapy (e.g., BDNF, VEGF modulation), CRISPR-based editing of MMP-9, and pharmacogenomics targeting ABCB1 and CYP2C19 variants. Conclusion: Genetic regulation of BBB integrity involves complex interactions among tight junction, inflammatory, and angiogenic genes. Targeting CLDN5, MMP-9, VEGF, and IL-6 pathways offers promising therapeutic avenues for ischemic stroke. Future research should focus on safe gene delivery and personalized medicine approaches.