Protein-protein interaction occurs transiently or stably when two or more proteins bind together to mediate a wide range of cellular processes such as protein modification, signal transduction, protein trafficking, and structural folding. The macromolecules involved in protein biosynthesis such as aminoacyl-tRNA synthetase (ARS) have a number of protein-protein interactions. The mammalian multi-tRNA synthetase complex (MSC) consists of eight different enzymes: EPRS, IRS, LRS, QRS, MRS, KRS, RRS, and DRS, and three auxiliary proteins: AIMP1/p43, AIMP2/p38, and AIMP/p18. The distinct ARS proteins are also connected to diverse protein networks to carry out biological functions. In this chapter we first show the protein networks of the entire MSC and explain how MSC components interact with or can regulate other proteins. Finally, it is pointed out that the understanding of protein-protein interaction mechanism will provide insight to potential therapeutic application for diseases related to the MSC network.