There is a continuing need for innovative, alternative therapies for hepatocellular carcinoma (HCC). Immunotherapy for cancer is attractive because of the exquisite specificity of the immune response. Activation of an HCC-specific response can be accomplished by strategies targeting tumor-associated self-antigens (for example, alpha-fetoprotein [AFP]). Gene array studies have added to the list of HCC-specific gene products that can be targeted. Alternatively, the immune response can be targeted against viral antigens in those patients infected with hepatitis B or C virus. Uncharacterized and mutated antigens can also be targeted with whole tumor cell or tumor lysate-based immunization strategies or with vectors coding for genes that make the tumor immunogenic, allowing the immune system to naturally evolve specificity against immunogenic target antigens. Strategies being investigated in animal models include increasing tumor immunogenicity by targeting cytokines or costimulatory molecules to tumor; immunization with tumor cells fused with antigen-presenting cells; adoptive transfer of viral antigen-specific T cells; and targeting AFP-expressing HCC cells by DNA, adenovirus, peptide, and dendritic cell (DC) strategies. Strategies that have been tested in human clinical trials include adoptive transfer of lymphocytes and autologous tumor-pulsed DC as well as 2 AFP-based strategies: AFP-derived peptides in Montanide and AFP peptides pulsed onto autologous DC. These trials, testing novel immune-based interventions in HCC subjects, have resulted in immunologic responses and have impacted recurrence and survival in HCC subjects.