AbstractThe number of effective systemic therapies for the treatment of unresectable hepatocellular carcinoma (uHCC) is rapidly increasing and the advent of immunotherapy changed the treatment paradigm for these patients, leading to a significant improvement in survival outcomes. While sorafenib, a tyrosine‐kinase inhibitor monotherapy, remained the only effective treatment for almost a decade, the combination of atezolizumab, an immune checkpoint inhibitor (ICI) targeting programmed death‐ligand 1, plus bevacizumab, an antiangiogenic agent targeting vascular endothelial growth factor, now represents the new standard of care for patients with uHCC. Moreover, several further clinical trials are ongoing to evaluate novel combinations between ICIs with other drugs, belonging to the same class or to other classes. As HCC occurs in most cases in the setting of cirrhosis, the evaluation of the risk/benefit ratio of systemic treatments represents a critical point. The underlying liver disease significantly influences the safety and the effectiveness of current and future systemic treatments for uHCC. For this reason, the hepatotoxicity profile and impact on liver function of these molecules should be carefully assessed in both clinical trials and in the real‐world setting. Here, we review hepatotoxicity data on systemic treatments for uHCC and offer suggestions on monitoring and managing liver‐related adverse events occurring during the treatment.