T cell immunity is critical for a protective immune response against cancers. Traditionally, this function has been ascribed to CD8 T lymphocytes with cytotoxic activity, which are restricted by MHC class I molecules. The lack of direct cytolytic effector function on part of CD4 T cells, which are MHC class II restricted, coupled with the MHC class II negative nature of most human cancers have been the main reasons for CD8 centered cancer immunotherapy approaches, so far. However, recent findings showing that CD4 T cells play an essential role towards the generation of a productive CD8 response and that the CD4 T cells can also play a direct role in anti-tumor immunity have resulted in growing enthusiasm towards engaging CD4 T cells in cancer immunotherapy. We here discuss the current approaches used for immune based cancer therapy, role of natural MHC class II-restricted CD4 T cells in tumor immunity, factors limiting the engagement of natural CD4 T cells in cancer immunotherapy protocols alongside CD8 T cells, and recent advances in TCR engineering approach to address these limitations. We will also discuss the significance of the MHC class I directed antitumor CD4 T cells in tumor immunity.