Receiving both portal vein blood and arterial blood, the liver is an important and critical component in the defense against blood-borne infection. To accomplish this role, the liver contains numerous innate and adaptive immune cells that specialize in detection and capture of pathogens from the blood. Further, these immune cells participate in coordinated immune responses leading to pathogen clearance, leukocyte recruitment and antigen presentation to lymphocytes within the vasculature. Finally, this role in host defense must be tightly regulated to ensure that inappropriate immune responses are not raised against nonpathogenic exogenous blood-borne molecules, such as those derived from food. It is this balance between activation and tolerance that characterizes the liver as a frontline immunological organ.