Kupffer cells (KCs) are macrophages that reside in sinusoids in proximity to ECs. They serve a physiological function to remove senescent cells and particulates, including bacteria and their products. Kuffer Cells are a critical component of the mononuclear phagocytic system and are central to both the hepatic and systemic response to pathogens. KCs are reemerging as critical mediators of both liver injury and repair, residing within the lumen of liver sinusoids. Their main function is to remove cellular debris and invading pathogens. KCs protect the liver by responding to pathogens and metastatic cells, whilst tolerating harmless self and foreign antigens. Kupffer Cells play an important role in fibrosis, liver inflammation, alcoholic liver disease, fatty liver disease, liver transplantation and more. Mouse Kupffer Cells provide an invaluable tool for understanding physiological and pathophysiological relevance in liver function and disease.