Human Kupffer Cells (HKC) are hepatic macrophages which derive from circulating bone marrow-derived monocytes. The main function of macrophages is to remove cellular debris and destroy invading pathogens. They reside within the lumen of liver sinusoids. HKC protect the liver by responding to pathogens and metastatic cells, while tolerating harmless self and foreign antigens, which enter via blood flow through the portal vein and hepatic artery. Human Kupffer Cells play an important role in diseases such as fibrosis, liver inflammation, fatty liver disease, and liver transplantation. HKC are an excellent model for studying macrophage functions under normal physiological and pathological conditions.