Systemic chemotherapy for hepatocellular carcinoma (HCC) has been of limited value in clinical practice, because only a small portion of patients obtain significant effects, and because the toxicity of chemotherapy often outweighs the benefits. Therefore, at present, only HCC patients with no indication for standard treatments (surgical resection, percutaneous ethanol injection and transcatheter arterial embolization) undergo chemotherapy. Due to the causes of death, tumor response and survival rate, only patients with metastatic sites other than in the bone, patients with no tumor thrombus in the main portal trunk and with good hepatic reserve are good candidates for systemic chemotherapy. To improve the prognosis in HCC patients, effective chemotherapy must be developed. The recommended strategy is to include all patients with advanced HCC in well-designed phase II trials with novel anti-cancer agents or regimens, when patients can tolerate treatment. Furthermore, prospective randomized trials comparing systemic chemotherapy with other palliative therapies or the best supportive care for HCC, are necessary before a clinically available chemotherapeutic regimen can be recommended for HCC.