The induction of adaptive immune responses critically depends on helper signals provided by CD4(+) T cells. These signals not only license antigen presenting cells (APC) to activate naïve CD8(+) T cells leading to the formation of vast numbers of cytotoxic T lymphocytes but also support the differentiation of B cells into immunoglobulin-secreting plasma cells. Next to these helper functions, a subpopulation of CD4(+) T cells can also directly function as effector cells by executing cytotoxicity in a peptide-specific and MHC class II-restricted manner. Cytotoxic CD4(+) T cells may function in combating pathogens but additionally their presence has been associated with autoimmune disease and vascular damage. On the contrary, the induction of cytotoxic CD4(+) T cells may be a future target for vaccine strategies.