Our knowledge on the physiological role of CD4(+) T lymphocytes has improved in the last decade: available data convincingly demonstrate that, besides the 'helper' activity, CD4(+) T cells may be also endowed with lytic properties. The cytotoxic function of these effector cells has a relevant role in the control of pathogenic infections and in mediating antitumor immune responses. On these bases, several immunotherapeutic approaches exploiting the cytotoxic properties of CD4(+) T cells are under investigation. This review summarizes available data supporting the functional and therapeutic relevance of cytotoxic CD4(+) T cells, with a particular focus on Epstein-Barr virus (EBV)-related disorders.