The cell-invasive, trypomastigote form of Trypanosoma cruzi exhibits a unique relationship with lysosomes in target host cells. In contrast to many intracellular pathogens that are adept at avoiding contact with lysosomes, T. cruzi requires transient residence within this acidic organelle for productive infection. The low pH environment of lysosomes facilitates parasite egress from the vacuole and delivery into the host cytosol, a critical step in the T. cruzi developmental program. Recent studies also suggest that early lysosome fusion with invading or recently internalized parasites is critical for cellular retention of parasites. To ensure targeting to host cell lysosomes, T. cruzi trypomastigotes exploit two distinct modes of invasion that rapidly converge in the cell. In this chapter, we summarize the recent progress and changing views regarding the role of host cell lysosomes in the T. cruzi infection process where our discussion is limited to invasion of nonprofessional phagocytic cells.