Natural killer (NK) cells play an important role in the immune response to viral infection and tumors.The ability of NK cells depends on the integrated signals across the array of stimulatory and inhibitory receptors engaged upon interaction with target cell surface ligands. Some stimulators, including viruses, tumor cells and hot shock, could promote the expression of NKG2 receptors and their ligands via activating certain transcription factors which are capable of up-regulating NKG2 promoters' activity. Meanwhile, epigenetic mechanisms including DNA methylation and histone posttranslational modifications are also critical to expression of NKG2 receptors and their ligands and may control the clonally distribution of some NK cell receptors. Investigating the epigenetic mechanisms of NK cell receptors and their ligands might helpful to the rational design of therapy against infection, inflammation, cancer or autoimmune diseases.