Over the past several decades, primary liver cancer (PLC), mostly hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA), has become the focus of rising concern mainly due to the increasing rates of incidence and high global mortality. Immunotherapy, as an emerging treatment approach, represents an effective and promising option against PLC. However, the selection of immunotherapeutic targets while considering tumor heterogeneity and immunosuppressive tumor microenvironment is a major challenge. The purpose of this review is to summarize and present the emerging immunotherapeutic targets for HCC and iCCA and to evaluate their translation advances in currently ongoing clinical trials. To better provide a framework for the liver cancer target selection, this chapter will highlight cell surface antigens expressed in both tumor cells and immune cells. Particular focus will be on the development, biology and function of Glypican-3 (GPC3) and Mesothelin (MSLN) in the cancer progress of HCC and iCCA, respectively. By doing so, we will explore the prospects and applications of various immunotherapeutic strategies such as vaccines, monoclonal antibodies, immunotoxins, antibody-drug conjugates (ADCs) and chimeric antigen receptors (CARs) T cells that have been developed targeting GPC3 and MSLN.