Hepatocellular carcinoma is a challenging disease to treat because of its association with cirrhosis, variable biologic behavior, and variable morphology and because of the variations in local expertise and resources available. The expertise of multiple specialties is required for optimal treatment, which must be individualized. Multidisciplinary and multimodality approaches can be successful for converting patients with unresectable disease into surgical candidates and can stabilize disease as patients await liver transplantation. Regional and local ablation treatment strategies provide effective palliation and possibly prolong survival in nonsurgical candidates, with novel combinations of therapies showing promising results. Interventional radiologists can and should play a lead role in the multidisciplinary management of this disease and in the development of future treatment strategies.