Proteins rarely act alone. With the development of experimental technologies, researchers have started to map the interactions of proteins in different organisms. The data gathered constitute potential frameworks for system-based drug discovery. The possibility of targeting protein-protein interactions with specific drugs raises expectations of huge impact in the therapeutics field, despite the large quantity of research still necessary to delineate the complete interactome of a single cell. This review summarizes some concepts relating to protein-protein interfaces in relation to drug discovery, and discusses studies aiming to develop protein-protein interaction modulators through the combination of in silico and in vitro screening experiments.