New findings show that natural killer (NK) cell activity is modulated by exogenous (including dietary) and endogenous ligands for the aryl hydrocarbon receptor (AHR). AHR was found to be mainly expressed by conventional splenic NK cells following cytokine stimulation. Despite having normal development and maturation, NK cells from AHR-deficient mice had poor cytotoxic activity compared with NK cells from wild-type mice. Indeed, NK cells in AHR-deficient mice failed to protect against the growth of RMA-S tumours. The administration of the endogenous AHR agonist FICZ (6-formylindolo[3,2-b]carbazole) to RMA-S tumour-bearing wild-type mice enhanced NK cell control of tumour growth but had no effect in AHR-deficient mice. NK cells from the FICZ-treated wild-type mice produced more interferon-γ and had a greater cytotoxic capacity than NK cells from untreated mice. The finding that various AHR ligands could also modulate human NK cells suggests new ways to activate NK cells in therapeutic settings.