Trypanosoma cruzi trans-sialidase is a potential target for Chagas disease chemotherapy. From the specific need of T. cruzi to obtain sialic acid through trans-sialidase-mediated transfers from host sources and the lack of alternative to this for the parasite, a good case can be made for T. cruzi trans-sialidase to serve as a potential drug target against Chagas disease. This review deals with both the particular aspects relevant to T. cruzi trans-sialidase as a target and generalises the situation for drug design in its broader aspects on the basis of some special problems in terms of rational drug design that T. cruzi trans-sialidase raises, particularly those of multiple gene copies and active site plasticity.