Natural killer (NK) cells are enriched in lymphocytes within the liver and have unique phenotypic features and functional properties, including tumor necrosis factor–related apoptosis-inducing ligand–-dependent cytotoxicity and specific cytokine profiles. As a key component of innate immunity in the liver, NK cells perform critical roles in host defense against pathogens and tumors through their natural cytotoxicity and cytokine production, and they also act as regulatory cells by engaging in reciprocal interactions with other types of liver cells through cell-to-cell contact and the production of cytokines. Accumulating evidence from the last decade suggests that NK cells play an important role in controlling viral hepatitis, liver fibrosis, and liver tumorigenesis, but also contribute to the pathogenesis of liver injury and inflammation. The characterization of intrahepatic NK cell functions has not only helped us to better understand the pathogenesis of liver disease, but has also revealed new therapeutic targets for managing this disease. (HEPATOLOGY 2013;57:1654–1662)