Hepatocellular carcinoma (HCC) is a common cancer with unmet needs and limited effective therapeutic options. The management strategy for diagnosed HCC is based on Barcelona Clinic Liver Cancer (BCLC) staging. Advanced HCC is treated with systemic therapy comprising oral tyrosine kinase inhibitors (TKIs) and intravenous immune checkpoint inhibitors, provided that liver function is reasonable. Five new agents have been approved by the US Food and Drug Administration (FDA) in the past 2 years for the treatment of HCC: lenvatinib in the first-line setting, and regorafenib, nivolumab, pembrolizumab, and cabozantinib as second-line therapies. The FDA is considering a label expansion of ramucirumab to include its use in HCC. These therapies have all been shown to extend overall patient survival and appear to have a reasonable safety profile. Multiple ongoing trials are studying immune checkpoint inhibition alone or in combination with TKIs. The results of these trials will help determine the optimal choice, timing, and sequence of agents. This article reviews the role of currently approved systemic therapies for HCC and highlights potential future combination therapeutic strategies. The article also brings forward the concept of a developing shift to the left for therapy, as mapped out in the BCLC staging and treatment algorithm, marking earlier use of systemic therapy prior to advanced progression of the disease.