Natural killer (NK) cells have a crucial role in combating infections and cancers and their surface receptors can directly recognize and respond to damaged, transformed or non-self cells. Whereas some virus-infected cells are recognized by this same route, NK-cell responses to many pathogens are triggered by a different mechanism. Activation of NK cells by these pathogens requires the presence of accessory cells such as monocytes, macrophages and dendritic cells. Recent studies have identified numerous pathogen-recognition receptors that enable accessory cells to recognize different pathogens and subsequently transmit signals--both soluble and contact-dependent--to NK cells, which respond by upregulating their cytotoxic potential and the production of inflammatory cytokines.