The liver is a unique anatomical and immunological site in which antigen‐rich blood from the gastrointestinal tract is pressed through a network of sinusoids and scanned by antigen‐presenting cells and lymphocytes. The liver's lymphocyte population is selectively enriched in natural killer and natural killer T cells which play critical roles in first line immune defense against invading pathogens, modulation of liver injury and recruitment of circulating lymphocytes. Circulating lymphocytes come in close contact to antigens displayed by endothelial cells, Kupffer cells and liver resident dendritic cells in the sinusoids. Circulating lymphocytes can also contact hepatocytes directly, because the sinusoidal endothelium is fenestrated and lacks a basement membrane. This unique anatomy of the liver may facilitate direct or indirect priming of lymphocytes, modulate the immune response to hepatotrophic pathogens and contribute to some of the unique immunological properties of this organ, particularly its capacity to induce antigen‐specific tolerance. (Hepatology 2006;43:S54–S62.)