Every year, more than 800 Mio people die from hepatocellular cancer (HCC) worldwide making HCC one of the deadliest diseases in the world. Standard of care treatment options are limited and very distinct from other types of solid cancer including surgical resection, orthotopic liver transplantation, local ablative therapies, transarterial chemoembolization, and radiation and systemic therapy with TKIs. More than 80% of patients with HCC have different types of underlying liver diseases causing possible liver dysfunction making treatment of this disease much diffcult. Despite efforts from basic scientist, clinical investigators, biotech companies, and biopharma, very little progress has been made in the past 10 years. However, this may change with the advent of immunotherapy in medical oncology. There is good preclinical and clinical data suggesting that immune-based approaches may be benefcial for the treatment of patients with HCC. One should not forget that HCC is an inflammation-induced cancer and therefore may be a good candidate for immunebased approaches. As a matter of fact, HBV vaccination can be considered the frst successful preventive cancer vaccine. The increasing interest on immune-based approaches is reflected by an increased number of publications investigating immunological mechanisms in HCC (Fig. 1).