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Simple Summary: Hepatocellular carcinoma is the fourth leading cause of cancer-related mortality worldwide and a major health problem. Overall survival is poor, with a five-year relative survival rate of 18.4% and only 2% in metastatic hepatocellular carcinoma. In 2020, the combination of atezolizumab and bevacizumab improved survival compared to sorafenib and was validated as the first-line treatment for advanced hepatocellular carcinoma. In case of disease progression, regorafenib and cabozantinib are recommended in the second-line setting. Transarterial chemoembolization can also be proposed for downstaging or in the palliative setting. Being able to reliably estimate liver function is a major issue in therapeutic management because patients with intermediate liver function are no longer eligible to receive systemic treatments. The aim of this review was to discuss systemic treatment management for patients with advanced unresectable HCC for whom liver-directed therapy is not appropriate. Hepatocellular carcinoma (HCC) usually occurs in the setting of liver cirrhosis and more rarely in a healthy liver. Its incidence has increased in the past years, especially in western countries with the rising prevalence of non-alcoholic fatty liver disease. The prognosis of advanced HCC is low. In the first-line setting of advanced HCC, sorafenib, a tyrosine kinase inhibitor, was the only validated treatment for many years. In 2020, the combination of atezolizumab, an immune checkpoint inhibitor, and bevacizumab showed superiority to sorafenib alone in survival, making it the first-line recommended treatment. Regorafenib and lenvatinib, other multikinase inhibitors, were also validated in the second and first-line settings, respectively. Transarterial chemoembolization can be an alternative treatment for patients with intermediate-stage HCC and preserved liver function, including unresectable multinodular HCC without extrahepatic spread. The current challenge in advanced HCC lies in the selection of a patient for the optimal treatment, taking into account the underlying liver disease and liver function. Indeed, all trial patients present with a Child–Pugh score of A, and the optimal approach for other patients is still unclear. Furthermore, the combination of atezolizumab and bevacizumab should be considered in the absence of medical contraindication. Many trials testing immune checkpoint inhibitors in association with anti-angiogenic agents are ongoing, and primary results are promising. The landscape in advanced HCC management is undergoing profound change, and many challenges remain for optimal patient management in the years to come. This review aimed to provide an overview of current systemic treatment options for patients with advanced unresectable HCC who are not candidates for liver-directed therapy. [ABSTRACT FROM AUTHOR]