While CD8+ cytotoxic T cells have long been considered the primary effector in controlling tumors, the involvement of CD4+ "helper" T cells in anti-tumor immunity has been underappreciated. The investigations of intra-tumoral T cells, fueled by the recent advances in genomic technologies, have led to a rethinking of the indirect role of CD4+ T cells that have traditionally been described as a "helper". Accumulating evidence from preclinical and clinical studies indicates that CD4+ T cells can acquire intrinsic cytotoxic properties and directly kill various types of tumor cells in a major histocompatibility complex class II (MHC-II)-dependent manner, as opposed to the indirect "helper" function, thus underscoring a potentially critical contribution of CD4+ cytotoxic T cells to immune responses against a wide range of tumor types. Here, we discuss the biological properties of anti-tumor CD4+ T cells with cytotoxic capability and highlight the emerging observations suggesting their more significant role in anti-tumor immunity than previously appreciated. [BMB Reports 2023; 56(3): 140-144].