Medical therapy for hepatocellular carcinoma (HCC) is an area of active investigation because fewer than 25% of patients are candidates for curative resection or transplantation. Single agent doxorubicin, the former standard of care, generated a 10% tumor response but resulted in substantial toxicity. The resulting recommendation of the NCCN has been to administer cytotoxic chemotherapy only under clinical protocol. More recently, newer drugs with more specific targets have forced re-consideration of palliative chemotherapy in clinical practice. Bevacizumab is a promising therapy but data is limited to Phase 2 trials without impressive results. Sorafenib is the prototype multi-kinase inhibitor, which has demonstrated some but limited survival benefit in advanced HCC. This has subsequently become the standard of care. Epidermal growth factor receptor, the target of rapamycin (mTOR) pathway, transforming growth factor-β, and cyclin-dependent kinases have been recent targets of ongoing study for potential therapeutics. Overall, current therapeutics have been so promising that adjuvant therapy after curative treatment in under investigation to reduce recurrence.