Understanding how drugs interact with their target proteins is fundamental to the development of effective therapeutics. Most drugs act by binding to specific proteins involved in diseases or key biological pathways, thereby modulating their activity. When high-resolution structural information of a protein–drug complex is available, it enables detailed elucidation of the drug’s mechanism of action. Such structural insights also facilitate rational design and optimization of molecules that more effectively bind to the target protein to either enhance or inhibit its function. This chapter focuses on cytochrome c oxidase (CcO), the terminal oxidase of the mitochondrial respiratory chain, as a model system to illustrate structure-based drug discovery. CcO plays a central role in cellular energy production, and its activity is tightly regulated in response to metabolic demands. By examining recent advances in high-resolution structural studies of CcO in complex with small molecules, we highlight how structural biology can inform and accelerate the development of new therapeutic strategies.