The liver is an organ with unique immune regulatory potential. This review highlights the experimental evidence for the involvement of hepatic cell populations in the induction of oral tolerance. Although immune tolerance towards oral antigens is mainly induced in the gastrointestinal tract within gut associated lymphatic tissue via generation of regulatory CD4 T cells, there is a further need for tolerance induction outside the gastrointestinal tract, because oral antigens rapidly distribute within minutes systemically through the blood stream. Besides hepatic dendritic cells, liver sinusoidal endothelial cells are active in the uptake and cross-presentation of oral antigens from portal venous blood and engage in the induction of CD8 T cell tolerance towards these antigens. These reports strengthen the notion that the liver participates in the induction of oral tolerance.