Development of liver metastases is a frequent complication in the course of gastro-intestinal malignancies. After entering the liver via the portal circulation, blood-borne tumor cells that have been seeded from primary colorectal cancer, are first encountered by Kupffer cells (KC), which line the liver sinusoids. KC represent approximately 10% of all liver cells, and have the ability to kill tumor cells. As such, they may play an important intrinsic role in the protection against outgrowth of hepatic metastases. Furthermore, the cytotoxic function of KC is increased upon stimulation with various biological response modifiers, such as interferon-gamma, granulocyte macrophage-colony stimulating factor, antibodies and muramyl dipeptides. Therefore, enhancement of KC cytotoxic functions may represent an attractive treatment modality to prevent development of liver metastases in the clinical setting.