Protein assemblies are currently poorly represented in structural databases and their elucidation is a key goal in biology. In particular, the ability to control protein-protein interactions therapeutically is of great current interest due to the many important processes involving these interactions. Recently, we have analysed clefts on protein surfaces, likely to correspond to binding ‘hot-spots’ according to properties thought to be important in stabilizing the native complex. This includes, sequence conservation and measures of physical properties including hydrophobicity, desolvation, electrostatic and van der Waals potentials. The resulting differences between predicting binding-sites at protein–protein and protein–ligand interfaces are striking. Generally, the prediction accuracy for protein–protein interfaces is lower. The talk will describe a number of structural bioinformatics tools for prediction and characterisation of protein binding sites, and discus the potential for targeting protein-protein interactions with small molecule drugs.