Hepatitis B virus(HBV) infection is the leading cause of liver disease and hepatocellular carcinoma(HCC) worldwide, in spite of prophylactic vaccination and antiviral treatment modalities. The immunopathogenesis of HBV infection has been intensively studied and ispropelled by complex interactions between the virus and the host immune system. Natural killer group 2D(NKG2D) is a well-characterized activating receptor, expressed on natural killer(NK) cells, NK T cells and CD8+ cytotoxic T cells. This receptor is present in both humans and mice and binds to a diverge family of ligands that resemble the MHC-class?Ⅰ?molecules. Increasing evidence shows that NKG2D-ligand interactions are critical in the establishment of HBV persistence and the development of liver injury and HCC. The expression of NKG2 D ligands depends on the presence of several polymorphisms and is also modulated post-transcriptionally by HBV. While it is known that HBV circumvents host’s innate immunity via the NKG2 D pathway but the exact mechanisms involved are still elusive. This letter discusses previous accomplishments on the role of NKG2 D ligand regulation in the development of chronic HBV, liver injury and HCC. The immunopathogenesis of HBV infection has been intensively studied and ispropelled by complex interactions between the virus and The host immune system. Natural killer group 2D (NKG2D) is a well-characterized activating receptor, expressed on natural killer (NK) cells, NK T cells and CD8 + cytotoxic T cells. This receptor is present in both humans and mice and binds to a diverge family of ligands that resemble the MHC-class? I molecules. Increasing evidence shows that NKG2D-ligand interactions are critical in the establishment of HBV persistence and the development of liver injury and HCC. The expression of NKG2 D ligands depends on the presence of several polymorphisms and is also modulated post-transcriptionally by HBV. While it is known that HBV circumvents host’s innate immunity via the NKG2 D pa Thway but the exact mechanisms involved are still elusive. This letter discusses previous achievements on the role of NKG2 D ligand regulation in the development of chronic HBV, liver injury and HCC.