Treatment options for patients with hepatocellular carcinoma (HCC) are rapidly changing based on positive results from phase 3 trials of targeted and immune-based therapies. More agents designed to target specific pathways and immune checkpoints are in clinical development. Some agents have already been shown to improve outcomes of patients with HCC, as first- and second-line therapies, and are either awaiting approval by the Food and Drug Administration or have been recently approved. We summarize the targeted and immune-based agents in trials of patients with advanced HCC and discuss the future of these strategies for liver cancer.