We have recently witnessed substantial progress with immunotherapy for selected diseases. Checkpoint inhibitors and chimeric antigen receptor T (CAR-T) cells are among the most promising agents. Whereas much of the early success with CAR-T cells has been demonstrated with hematological malignancies, important barriers remain for the application of CAR-T cell therapies for the management of metastatic solid tumors. The challenges are particularly apparent when considering primary and metastatic tumors in the liver. At baseline, the intrahepatic space is immunosuppressive and this feature is exploited by malignant cells. Fortunately, our evolving understanding of liver immune cell biology is allowing the development of novel immunotherapeutic strategies for the treatment of liver tumors. Furthermore, the unique anatomic features of the liver make possible highly selective immunotherapeutic delivery approaches that may maximize antitumor efficacy while limiting off-target damage to healthy tissues. This review summarizes the immunobiology of the intrahepatic space and how this knowledge enables identification of hurdles and potential solutions to the barriers facing immunotherapy for liver tumors.