Kupffer cells are resident liver macrophages and play a critical role in maintaining liver function. Under physiological conditions, they are the first innate immune cells that protect the liver from bacterial infection. Under pathological conditions, they are activated by different components and can differentiate into M1-like (classical) or M2-like (alternative) macrophages. The metabolism of classical or alternative activated Kupffer cells will determine their function in liver damage. Special function and metabolism of Kupffer cells suggest that they are an attractive target for the treatment of liver inflammation and related diseases, including cancer and infectious diseases.