MHC class I–restricted tumor antigens can be presented to CD8⁺ T cells by two distinct pathways: via direct and indirect presentation. The relative contribution of these two pathways toward the initial activation of tumor antigen–specific CD8⁺ T cells and their subsequent tumor rejection is still vigorously debated. Using a tumor model able to dissect the relative contributions of direct and indirect presentation, we show unequivocally the inefficiency of direct presentation and the essential requirement of indirect presentation for the priming of naive tumor antigen–specific T cells leading to tumor rejection. Moreover, we characterize the essential environment under which indirect presentation occurs, and find efficient cross-priming of tumor-specific CD8⁺ T cells in the complete absence of secondary lymphoid tissues. The independence of this process from local lymph nodes is compromised, however, in the absence of CD4⁺ T cell help. Therefore, our paper demonstrates that effective immune protection against tumors requires the cross-priming of CD8⁺ T cells under conditions that require either CD4⁺ T cell help, or draining lymph nodes.