Basic and clinical studies have demonstrated the efficacy of immunotherapy, a technical and conceptual breakthrough that has revolutionised cancer treatment. Hepatocellular carcinoma (HCC), a deadly malignancy with aetiologic diversity and a chronic course, is strongly influenced by the immune system, and was recently found to partially benefit from immune-checkpoint inhibitor therapy. Notably, HCC onco-immunology depends on diverse genetic and environmental factors that together shape cancer-promoting inflammation and immune dysfunction – critical processes that control HCC malignant progression and response to therapy. Herein, we summarise the current understanding of liver and HCC onco-immunology obtained through basic studies with mouse models and clinical practice in humans. In particular, we discuss preclinical and clinical findings that implicate immunomodulation as a major factor in HCC development and explain the basis for HCC-targeting immunotherapy.