Here we review the use of informatics in structural interactomics, with particular emphasis on understanding interfacial contacts in the development of novel therapeutics and the interpretation of genetic variation. We describe the availability and applicability of structural databases of protein interactions which facilitate this endeavour. We demonstrate the applicability of a structural interactomics approach to the study of the fibroblast growth factor (FGF)-stimulated mitogen-activated protein kinase (MAPK) pathway.