Abstract: The incidence and mortality rates of liver cancer are among the highest reported for malignant tumors worldwide. Most patients with hepatocellular carcinoma (HCC) present with advanced stage disease at initial diagnosis, which precludes the option of radical surgery. Systemic therapy is the main treatment option for such patients. In recent years, a variety of immune checkpoint inhibitors (ICIs) have emerged and have been approved for use in advanced HCC. ICIs in combination with anti-angiogenic agents have been shown to be more effective than ICIs alone. However, most patients still cannot benefit from either ICI monotherapy or the combination of ICIs and anti-angiogenic agents. The choice of the appropriate treatment, according to the specific treatment goals for each patient, and of different biomarkers is one of the current challenges in clinical practice. In this review, we summarize the current state of research on the use of ICIs alone and ICI-based combination therapies using different drugs and local therapies, the use of biomarkers for predicting the efficacy of therapy and patient prognosis, and drug resistance to ICIs alone and ICI-based combination therapies.