There are few treatment options for advanced-stage hepatocellular carcinoma (HCC). Targeting tumor-associated antigens (TAAs) for HCC immunotherapy has been tested clinically for many years with limited success. Recent advances in applying mutated tumor-specific neoantigens as immunotherapeutic targets raise hope that this class of antigens may be used in HCC treatment. Accordingly, multiple clinical trials have been initiated to test this concept. However, recent findings demonstrate that mutated neoantigens are rarely detected while unmutated antigens derived from TAAs are represented in the HLA ligandomes of HCC patients, suggesting a requirement to target TAAs for HCC immunotherapy. Herein, we review the potential pitfalls of previous clinical applications of targeting TAAs in HCC immunotherapy. Based on further understanding of the roles of different arms of adaptive immunity in antitumor immunity, we provide a perspective on how to address the unsatisfactory previous immunotherapy attempts in HCC. We propose a new vaccine platform that enhances all three arms of the adaptive immune system to improve TAA-based cancer vaccination in HCC patients. As many solid tumors with low and intermediate mutation burdens have similar TAA and neoantigen expression and presentation patterns, the new vaccine platform is broadly applicable. In conclusion, targeting TAA in HCC for immunotherapy is necessary and new strategies are needed to improve clinical efficacy.This article is protected by copyright. All rights reserved.