Hepatocellular carcinoma (HCC) is a disease that is extremely difficult to manage and is increasing markedly in incidence. This presents both an opportunity and a challenge. At-risk patients can be identified and early detection of HCC is feasible. New surgical techniques and postoperative therapies, including hepatic intra-arterial radiation, may improve the outlook for some patients with resectable cancer. Unfortunately, the vast majority of patients with HCC will have unresectable cancers. Regional treatments may shrink or necrose tumors, but no clear benefit to such therapies has been demonstrated. Recent evidence suggests combination chemotherapy may help some patients, although this needs validation. Perhaps the best hope is that the further elucidation of the genetic and molecular features of HCC will lend us insight into innovative strategies to manage this difficult cancer.