The protozoan parasite Trypanosoma cruzi must enter cells of its vertebrate host in order to replicate. Once this is accomplished, the infective trypomastigotes can invade many different cell types from several host species. This observation is in agreement with the parasite's wide natural host range. Studies performed with cultured mammalian cells in vitro have shown that T. cruzi invasion is an unusual process, distinct from phagocytosis, that depends on parasite energy and on negatively charged surface molecules of the host cell. Several surface glycoproteins and mucin-like molecules of trypomastigotes have been implicated, mainly by inhibition studies with antibodies, in interactions with host cells. Recently, several of the trypomastigote surface glycoproteins were shown to be related members of a large family that includes the T. cruzi trans-sialidase. The mucin-like molecules are beginning to emerge as a separate family of threonine-rich, O-glycosylated molecules that function as acceptors of sialic acid in the infective stages. Several lines of evidence suggest that parasite surface molecules mediate binding to host cells, whereas invasion of nonphagocytic cells involves recruitment of host-cell lysosomes, an unusual event apparently triggered by signal transduction.