Over the past few years, the study of protein-protein interactions and protein complexes has shed more light on cellular processes and cell function. Because alterations in protein-protein interactions perturb the normal sequence of events in the cell and contribute to diseases such as cancer, the understanding of both the normal cellular protein-protein interaction networks and their modulation during the establishment of disease is a crucial issue in biomedical research, as it will facilitate the development of drugs to fight these diseases. In this article, the most commonly used approaches for studying protein-protein interactions are discussed as well as the direction in which the field of systematic characterization of protein interaction networks is progressing. We also discuss some success stories in the modulation of disease-related protein-protein interactions using small molecules.