Hepatocellular carcinoma (HCC) carries a dismal prognosis, with advanced disease being resistant to both radiotherapy and conventional cytotoxic drugs, whilst anti-angiogenic drugs are marginally efficacious. Oncolytic viruses (OV) offer the promise of selective cancer therapy through direct and immune-mediated mechanisms. The premise of OV lies in their preferential genomic replication, protein expression and productive infection of malignant cells. Numerous oncolytic viruses are being tested in pre-clinical models of HCC, with good evidence of direct and immune-mediated anti-tumour efficacy. Efforts to enhance the performance of these agents have concentrated on engineering OV cellular specificity, immune evasion, enhancing anti-tumour potency and improving delivery. The lead agent in HCC clinical trials, JX-594, a recombinant Wyeth strain Vaccinia virus has demonstrated evidence for significant benefit and earned orphan drug status. Thus, JX-594 appears to be transcending the barrier between novel laboratory science and credible clinical therapy. Otherwise, relatively few other OV have entered clinical testing, a hurdle that must be overcome if significant progress is to be made in this field. This review summarises the pre-clinical and clinical experience of OV therapy in the difficult-to-treat area of HCC.