There is increasing evidence that dendritic cells are capable of inducing T cell tolerance to tissue-specific antigens by presenting these antigens to CD4 and CD8 T cells in the respective draining lymph nodes. In contrast, parenchymal cells are often seen as immunologically inert. This lecture summarizes studies showing that tissue cells like sinusoidal endothelial cells and hepatocytes in the liver as well as keratinocytes in the skin can induce peripheral T cell tolerance. This tolerance induction is often preceded by T cell activation. Thus, several tolerance mechanisms are operating in parallel. We still have no learn which mechanism is most suitable for therapeutic intervention in autoimmune diseases and organ transplantation.