Hepatocellular carcinoma (HCC) is a major worldwide health concern with an increasing incidence in the United States. Orthotopic liver transplantation (OLT) has been established as the gold standard for curative therapy of HCC. Because of limited organ supply and socioeconomic factors, OLT is often not a viable option. Surgical resection and ablation are also effective for providing long-term survival. However, most patients are ineligible for curative surgical therapy due to advanced disease. For these patients, effective treatment options have been lacking. Systemic chemotherapy and even recent biologic, targeted agents have shown little to minimal efficacy. Liver-directed regional therapies, including trans-arterial chemoembolization (TACE) and selective internal radiation treatment (SIRT) with Yttrium-90 radioembolization have emerged in recent years as effective therapies to provide local control of disease. Randomized trials have demonstrated a survival benefit for TACE, and SIRT has shown efficacy as an embolic alternative to TACE. Here we review the experience of liver-directed regional therapies and provide a clear rationale for their implementation in a multi-disciplinary algorithmic approach to the management of HCC.