Hepatocellular carcinoma (HCC) is a common cause of cancer mortality worldwide. Whilst local treatments are useful in selected patients, they are not suitable for many with advanced disease. Here, we review phase II and III trials for systemic therapy of advanced disease, finding no strong evidence that any chemotherapy, hormonal therapy, or immunotherapy regimen trialled to date benefits survival in this setting. Many trials were inadequately powered, single centre, and enrolled highly selected patients. From this review, we cannot recommend any therapeutic approach in these patients outside of a clinical trial setting. Including an untreated control arm in clinical trials in HCC is still justified. Every effort should be made to enroll these patients into adequately powered trials, and promising phase II results must be tested in a multicentre phase III setting, preferably against a placebo control arm. Prevention of hepatitis B and C remains vital to decrease deaths from HCC.