Despite recent developments in various chemotherapeutic agents and the performing of numerous clinical trials, chemotherapy still produces unsatisfactory results in hepatocellular carcinoma due to poor clinical benefit compared with untreated controls and its significant toxicity. The presence of liver cirrhosis, its complications, and decreased liver function increase the complexity of chemotherapy. There is recent evidence that targeted agents and antiangiogenic agents such as thalidomide are somewhat effective whilst having minimal toxicities. Some patients are cured by aggressive chemotherapy alone or in combination with other modalities. Therefore, if a patient is in good condition and the tumor shows some response to chemotherapy, aggressive chemotherapy might be considered. Although conventional chemotherapeutic agents are not very effective in many patients, their utility might be improved by lowering toxicities using reduced doses or by selecting only responsive patients if adequate chemosensitivity tests are available. Imaging studies have been conventional tools for evaluating tumor responses, but their results are not always reliable. Establishing criteria for accurately determining tumor responses is urgently needed, along with better chemotherapeutic drugs and regimens.