Recent clinical trials and new agents have permitted greater clarity in the choice of effective agents for that majority of patients with hepatocellular carcinoma who have advanced disease at diagnosis and thus cannot be offered potentially curative resection, ablation or liver transplantation. The main treatment for these patients remains chemoembolization, although evidence for selective internal radiation therapy (SIRT) with SIR-Spheres or Theraphere, is beginning to suggest that the results with this may be comparable with less toxicity. Patients who have failed chemoembolization or SIRT or have metastatic disease at presentation are suitable for the multikinase inhibitor sorafenib (nexavar) or newly-approved lenvatinib (lenvima) as first line therapies. The choice between which of them to use first is not currently clear. Patients who have failed sorafenib can be offered a choice of FDA-approved regorafenib (stivarga) or immune checkpoint inhibitor nivolumab (opdivo) as second line agents. For that considerable percent of patients presenting with macroscopic portal vein thrombosis, the choice appears to be between multikinase inhibitor or SIRT, given the potential toxicity of chemoembolization in this setting. However, considering the potency of both nivolumab and regorafenib and the pipeline of new agents such as atezolizumab (tecentriq) in current clinical trials, including new immune checkpoint inhibitors, this landscape may change within a couple of years, especially if new evidence arises for the superior effectiveness of combinations of any of these agents over single agents.