The critical metabolic functions of the liver often eclipse any perception of its role as an immune organ. However, the liver as a mediator of systemic and local innate immunity and an important site of immune regulation is now an accepted concept. Complex repertoires of lymphoid and non-lymphoid cells are key to hepatic defense and immunoregulation. Hepatic cells of myeloid lineage include Kupffer cells and dendritic cells. Intrahepatic lymphocytes are distinct both in phenotype and function from their counterparts in any other organ and include both conventional (CD4+ and CD8+ αβ T cell receptor (TCR)+ T cells, B cells, natural killer (NK) cells) and nonconventional lymphoid cells (natural killer T (NKT) cells, γδTCR+ T cells, CD4− CD8− T cells). Many hepatic T cells express the TCR at an intermediate level and the great majority of them either coexpress NK cell markers (NKT cells) or they are apoptosing peripheral T cells. The percentage of activated (CD69+) and memory (CD45RBlow+) lymphocytes is much higher while naïve (CD62Lhigh) and resting T cells as well as B lymphocytes are underrepresented in the liver. The discovery of major populations of lymphoid cells in the liver that differ phenotypically, functionally and even perhaps developmentally from populations in other regions has been key to the evolving perception of the liver as a regulatory lymphoid organ. This chapter will focus on these populations and how they contribute to immune surveillance against malignant, infectious and autoimmune disease of the liver.