Multifunctionality of proteins is among mechanisms accounting for the complexity of interactome networks in higher eukaryotes. During oncogenesis and other pathologic conditions many proteins perform additional functions without changes in three dimensional structures. One family of these moonlighting proteins is represented by enzymes and cofactors of aminoacylation reactions, by means of which tRNAs are attached to their cognate amino acids. Tyrosyl-tRNA synthetase (TyrRS), tryptophanyl-tRNA synthetases (TrpRS) and auxiliary factor of mammalian multi-aminoacyl-tRNA synthetases, p43 (precusor of endothelial monocyte activating polypeptide II - EMAP II) upon their release in intracellular environment become proinflammatory cytokines with multiple activities during apoptosis, angiogenesis and inflammation. In addition, these proteins play important role in cancer progression, modulating tumor angiogenesis and its escape from surveillance by immune system.