This review by Irene M.A. Nooren and Janet M. Thornton from the European Bioinformatics Institute (EMBL-EBI) discusses the structural and functional diversity of protein-protein interactions (PPIs). PPIs play diverse roles in biology and can be categorized based on their composition, affinity, and whether they are permanent or transient. The review highlights the importance of the protomer's localization, concentration, and local environment in controlling the composition and oligomeric state of protein complexes. It also explores the structural characteristics of different types of PPIs and their relationship to physiological function, specificity, and evolution. The authors distinguish between homo- and hetero-oligomeric complexes, non-obligate and obligate complexes, and transient and permanent complexes. They explain how these types of interactions are controlled by altering local concentrations, binding affinity, and the local physicochemical environment. The review also discusses the structural characteristics of protein interfaces, noting that obligate complexes generally have larger and more hydrophobic interfaces compared to non-obligate associations. The specificity of PPIs is another key topic, with proteins often having specific binding partners due to shape and chemical complementarity. The review examines multispecificity within and between homologous protein families and the role of localization in determining specificity. Finally, the authors discuss the evolution of PPIs, suggesting that the structure and affinity of PPIs are tuned to their biological functions and physiological environments. They highlight the importance of understanding the underlying evolutionary, functional, and structural principles of PPIs to improve our ability to model and predict their structures and functions.This review by Irene M.A. Nooren and Janet M. Thornton from the European Bioinformatics Institute (EMBL-EBI) discusses the structural and functional diversity of protein-protein interactions (PPIs). PPIs play diverse roles in biology and can be categorized based on their composition, affinity, and whether they are permanent or transient. The review highlights the importance of the protomer's localization, concentration, and local environment in controlling the composition and oligomeric state of protein complexes. It also explores the structural characteristics of different types of PPIs and their relationship to physiological function, specificity, and evolution. The authors distinguish between homo- and hetero-oligomeric complexes, non-obligate and obligate complexes, and transient and permanent complexes. They explain how these types of interactions are controlled by altering local concentrations, binding affinity, and the local physicochemical environment. The review also discusses the structural characteristics of protein interfaces, noting that obligate complexes generally have larger and more hydrophobic interfaces compared to non-obligate associations. The specificity of PPIs is another key topic, with proteins often having specific binding partners due to shape and chemical complementarity. The review examines multispecificity within and between homologous protein families and the role of localization in determining specificity. Finally, the authors discuss the evolution of PPIs, suggesting that the structure and affinity of PPIs are tuned to their biological functions and physiological environments. They highlight the importance of understanding the underlying evolutionary, functional, and structural principles of PPIs to improve our ability to model and predict their structures and functions.