As the pivotal role of protein–protein interactions in cell growth, transcriptional activity, intracellular trafficking, signal transduction and pathological conditions has been assessed, experimental and in silico strategies have been developed to design protein–protein interaction modulators. State-of-the-art structure-based design methods, mainly pharmacophore modeling and docking, which have succeeded in the identification of enzyme inhibitors, receptor agonists and antagonists, and new tools specifically conceived to target protein–protein interfaces (e.g., hot-spot and druggable pocket prediction methods) have been applied in the search for small-molecule protein–protein interaction modulators. Many successful applications of structure-based design approaches that, despite the challenge of targeting protein–protein interfaces with small molecules, have led to the identification of micromolar and submicromolar hits are reviewed here.