CD4(+) T cells have the ability to differentiate into relatively specialized effector subsets after exposure to innate immune signals. The remarkable plasticity of CD4(+) T cells is required to achieve immune responses in different tissues and against various pathogens. Numerous studies have shown that CD4(+) T cells can play direct and indispensable roles in protective immunity by killing infected or transformed cells. Although the lineage decision of commitment to the CD4(+) or CD8(+) cell lineage is once thought to be inflexible, the identification of antigen-experienced CD4(+) T cells with cytotoxic activity suggests the existence of unexpected plasticity for these cells. The recognition of CD4(+) cytotoxic T lymphocytes (CTLs) and the mechanisms driving the differentiation of this particular cell subset create opportunities to explore the roles of these effector cells in protective immunity and immune-related pathology. CD4(+) CTLs are proven to play a protective role in antiviral immunity. Here, the latest investigations on the phenotypic and functional features of CD4(+) CTLs and their roles in antitumor immunity and immunotherapy are briefly reviewed.