The capability of killing various tumors or cells infected by certain viruses is a property shared by natural killer (NK) cells and by a subset of cytolytic T lymphocytes (CTLs) termed NK-CTL. Recent analysis of the molecular basis in these phenomena, however, revealed rather different molecular mechanisms. Thus, while NK cell cytotoxicity is regulated by a complex balance between activating signals (delivered by non HLA-class I-specific triggering receptors) and inhibitory signals (delivered by HLA-class I-specific receptors) the effector function of NK-CTL reflects the TCR-mediated recognition of the poorly polymorphic HLA-E.