This cross-journal Special Issue jointly by the Journal of Medicinal Chemistry and ACS Medicinal Chemistry Letters, highlights the transformative role of structural biology in drug discovery. Featuring global contributions from academia and industry, the Special Issue showcases structure-based approaches to developing therapeutics for infectious diseases, cancer, neurodegeneration, and cardiovascular conditions. It includes detailed studies on enzyme-ligand interactions, novel binding sites, and emerging drug modalities such as peptide mimetics and targeted protein degradation. We emphasize the global collaboration and foundational importance of structural insights in advancing medicinal chemistry.