JX-594 is a targeted oncolytic vaccinia virus designed to selectively replicate in and destroy cancer cells with epidermal growth factor receptor (EGFR)/ras pathway activation. Direct oncolysis plus granulocyte macrophage-colony stimulating factor (GM-CSF) expression is accompanied by tumor vascular shutdown and anti-tumoral immunity. In a Phase 1 trial, JX-594 injection into hepatocellular carcinoma (HCC) was well-tolerated and associated with viral replication, anti-cancer immunity, decreased tumor perfusion and tumor necrosis. JX-594 has been shown to be well-tolerated by intravenous (IV) infusion and intratumoral (IT) injection and JX-594 is being developed as a novel therapy for patients with refractory or advanced HCC. Synergistic anti-tumor effects are predicted with JX-594 and sorafenib due to acute vascular shut down effect and tumor-specific antibody formation of JX-594 and chronic anti-angiogenic effects of sorafenib. JX-594 shows promise as a novel agent for the treatment of advanced HCC.