CD4⁺ T cells contribute to tumor eradication, even in the absence of CD8⁺ T cells. Cytotoxic CD4⁺ T cells can directly kill MHC class II positive tumor cells. More surprisingly, CD4⁺ T cells can indirectly eliminate tumor cells that lack MHC class II expression. Here, we review the mechanisms of direct and indirect CD4⁺ T cell-mediated elimination of tumor cells. An emphasis is put on T cell receptor (TCR) transgenic models, where anti-tumor responses of naïve CD4⁺ T cells of defined specificity can be tracked. Some generalizations can tentatively be made. For both MHCII^POS and MHCII^NEG tumors, presentation of tumor-specific antigen by host antigen-presenting cells (APCs) appears to be required for CD4⁺ T cell priming. This has been extensively studied in a myeloma model (MOPC315), where host APCs in tumor-draining lymph nodes are primed with secreted tumor antigen. Upon antigen recognition, naïve CD4⁺ T cells differentiate into Th1 cells and migrate to the tumor. At the tumor site, the mechanisms for elimination of MHCII^POS and MHCII^NEG tumor cells differ. In a TCR-transgenic B16 melanoma model, MHCII^POS melanoma cells are directly killed by cytotoxic CD4⁺ T cells in a perforin/granzyme B-dependent manner. By contrast, MHCII^NEG myeloma cells are killed by IFN-γ stimulated M1-like macrophages. In summary, while the priming phase of CD4⁺ T cells appears similar for MHCII^POS and MHCII^NEG tumors, the killing mechanisms are different. Unresolved issues and directions for future research are addressed.