Medicinal chemistry plays a central role in modern drug discovery by integrating chemical principles with biological insights to design, optimize, and develop therapeutic agents. Among various approaches, structure-based drug design (SBDD) has emerged as a powerful and rational strategy that exploits three dimensional structural information of biological targets to guide ligand discovery and optimization. Advances in X-ray crystallography, nuclear magnetic resonance spectroscopy, cryo-electron microscopy, and computational modeling have significantly enhanced the accuracy and applicability of SBDD. This article provides a comprehensive overview of the principles of structure-based drug design, key experimental and computational techniques, and recent advances in medicinal chemistry applications. Challenges such as protein flexibility, resistance development, and translational limitations are critically discussed. Finally, emerging trends including artificial intelligence, machine learning, and integrated multi-omics approaches are highlighted as transformative tools shaping the future of medicinal chemistry and rational drug discovery.