It is clear that the mechanisms of invasion used by T. cruzi extracellular amastigotes, TCTs and metacyclic trypomastigotes are divergent. Added to this complexity is the finding of variation between isolates of the two main phylogenetic groups. The molecular information available for trypomastigote penetration, with the identification of putative ligands and their receptors, has not been paralleled in amastigote studies. So far, only a few parasite components, most of carbohydrate nature have been identified as important components for cell invasion. Emerging evidence suggest that these infective forms might, presumably by engaging different receptors, be trafficking in cytoplasmic compartments of distinct composition and maturation characteristics. The introduction of the companion pathogen, C. burnetii, has revealed new insights into these intricate processes. Mapping amastigote ligands and their putative receptors should provide molecular tools to explore these interactions in deeper detail. Also, the availability of GFP-tagged components acting in host cell endocytic and lysosomal pathways will offer the unique opportunity to carry out live cell experiments.