NKR and TLR are most important receptor superfamilies in innate immunity and act as first line of host defense against infection. Those receptors exert peculiar recognition mechanisms to sense danger signals and distinguish infectious nonself from noninfectious self. More importantly, they coordinate and regulate each other and therefore play major roles in initiation of innate immunity and also help to direct adaptive immune responses. The importance of recognition and interaction of those receptors are highlighted. The precise mechanisms can be harnessed to aid the rational design of therapy against infection, inflammation, cancer or autoimmune diseases.