Human NK cells in peripheral blood can be divided into at least two subsets based on the expression of CD56 and CD16. The major subset of CD56dimCD16+ NK cells constitutes ~90% of total blood NK cells, kills target cells upon proper recognition, and secretes only low levels of cytokines. CD56brightCD16− NK cells (<10% of total blood NK cells, but 75% of NK cells in secondary lymphoid tissues), in contrast, produce many cytokines, including IFN-γ, TNF, and GM-CSF, upon stimulation by proinflammatory cytokines, but acquire cytotoxicity only after prolonged activation. In addition, both subsets differ from each other with respect to expression of inhibitory and activating receptors. Although CD56brightCD16− NK cells express high levels of the inhibitory CD94/NKG2A complex recognizing HLA-E, they do not express MHC class I allele-specific killer cell Ig-like receptors that are, in contrast, expressed by CD56dimCD16+ NK cells. Moreover, only CD56brightCD16− NK cells express homing markers for secondary lymphoid organ (SLO), such as CCR7 and CD62L, and immature lymphocyte markers, such as c-KIT.