Simple SummaryHepatic and intrahepatic bile duct cancer is the sixth most frequently diagnosed cancer in the world. A total of 830,200 people died from liver cancer globally in 2020. It is estimated that hepatocellular carcinoma (HCC), an aggressive, primary malignant liver tumor, accounts for approximately 85% of all primary liver tumors. Despite the improvements in surveillance screening programs, the prevalence of HCC is expected to rise significantly over the coming decades. Beginning with the approval of sorafenib in 2007, there has been a monumental amount of progress attained in the management of advanced HCC with systemic therapies. Certain major gaps in therapy remain. This narrative review details the history, current landscape, and future directions of HCC systemic therapy. We hope this review will heighten interest in the field of HCC systemic therapies, provide a clear outline of the current data and strategy for treatment, and sensitize readers to new developments that are likely to emerge.AbstractWe provide a comprehensive review of current approved systemic treatment strategies for advanced hepatocellular carcinoma (HCC), starting with the phase III clinical trial of sorafenib which was the first to definitively show a survival benefit. After this trial, there was an initial period of little progress. However, in recent years, an explosion of new agents and combinations of agents has resulted in a markedly improved outlook for patients. We then provide the authors’ current approach to therapy, i.e., “How We Treat HCC”. Promising future directions and important gaps in therapy that persist are finally reviewed. HCC is a highly prevalent cancer worldwide and the incidence is growing due not only to alcoholism, hepatitis B and C, but also to steatohepatitis. HCC, like renal cell carcinoma and melanoma, is a cancer largely resistant to chemotherapy but the advent of anti-angiogenic, targeted and immune therapies have improved survival for all of these cancers. We hope this review will heighten interest in the field of HCC therapies, provide a clear outline of the current data and strategy for treatment, and sensitize readers to new developments that are likely to emerge in the near future.