CD8+ effector T cells recognize malignant cells by monitoring their surface for the presence of tumor-derived peptides bound to MHC class I molecules. In addition, tumor-derived Ags can be cross-presented to CD8+ effector T cells by APCs. IFN-γ production by CD8+ T cells is often critical for tumor rejection. However, it remained unclear whether 1) CD8+ T cells secrete IFN-γ in response to Ag recognition on tumor cells or APCs and 2) whether IFN-γ mediates its antitumor effect by acting on host or tumor cells. We show in this study that CD8+ effector T cells can reject tumors in bone marrow-chimeric mice incapable of cross-presenting Ag by bone marrow-derived APCs and that tumor rejection required host cells to express IFN-γR. Together, CD8+ effector T cells recognize Ag directly on tumor cells, and this recognition is sufficient to reject tumors by IFN-γ acting on host cells.