Trypanosoma cruzi trans-sialidase (TcTS) has intrigued researchers all over the world since it was shown that T. cruzi incorporates sialic acid through a mechanism independent of sialyltransferases. The enzyme has being involved in a vast myriad of functions in the biology of the parasite and in the pathology of Chagas' disease. At the structural level experiments trapping the intermediate with fluorosugars followed by peptide mapping, X-ray crystallography, molecular modeling and magnetic nuclear resonance have opened up a three-dimensional understanding of the way this enzyme works. Herein we review the multiple biological roles of TcTS and the structural studies that are slowly revealing the secrets underlining an efficient sugar transfer activity rather than simple hydrolysis by TcTS.