Most biological processes involve multiple proteins interacting with each other. The protein-protein interactions (PPIs) are the basis for almost all biological processes. Hot spots are residues comprising only a small fraction of interfaces yet accounting for the majority of the binding energy. These residues are critical in understanding the principles of PPI. The PIIMS Server (Protein Interface In silico Mutation Scanning) was developed successfully to predict hot spots from interface of protein-protein complex by calculating the binding free energy changes upon alanine mutation scanning. Additional, the mutation scanning strategy is introduced for understanding the impacts of hot spot mutations.