The blood-brain barrier (BBB) represents one of the most significant challenges in central nervous system (CNS) drug development, severely limiting therapeutic access to the brain. In vitro BBB models have emerged as indispensable tools for understanding barrier physiology and assessing drug permeability, offering alternatives to costly and ethically complex animal studies. This review examines the evolution of BBB modeling techniques, from simple monolayer cultures to sophisticated three-dimensional neurovascular unit reconstructions. Method development has progressed from immortalized cell lines like bEnd3 and hCMEC/D3 to primary brain endothelial cell cultures and advanced co-culture systems incorporating astrocytes, pericytes, and neurons. These models demonstrate enhanced barrier properties, including elevated transendothelial electrical resistance and reduced permeability coefficients, more closely mimicking in vivo conditions. Validation approaches encompass morphological assessments, functional barrier integrity measurements, and transporter activity evaluations using established reference compounds. Contemporary applications span high-throughput screening platforms for pharmaceutical discovery, mechanistic studies of transporter-mediated drug movement, and pathophysiological modeling of neuroinflammatory conditions. Emerging technologies, including microfluidic organs-on-chips and human induced pluripotent stem cell-derived models, promise improved physiological relevance and personalized medicine applications. Despite significant advances, current models face limitations in fully recapitulating the complex three-dimensional architecture and hemodynamic forces of the neurovascular unit. Nevertheless, these in vitro systems continue to provide valuable insights into BBB biology and serve as essential tools for CNS drug development, bridging the gap between molecular understanding and clinical translation.