An improvement of the chemotherapy of hepatocellular carcinoma with adriamycin or 5-fluorouracil and a reduction of side effects has been achieved by intra-arterial administration of the drugs. This treatment provides a somewhat extended survival but no cure. 2. The treatment of hepatocellular carcinoma in patients by reduction of an inactive precursor of a cytocidal alkylating agent by azoreductase of the tumor showed no therapeutic effect. 3. A selective hepatocellular uptake of drugs coupled to asialoglycoproteins has been described. An application of this concept for the chemotherapy of hepatocellular carcinoma seems doubtful since a loss of binding proteins for desialylated glycoproteins during experimental hepatocarcinogenesis has been demonstrated. 4. The increased uptake of 5-fluorouridine in hepatomas after induction of a tissue-specific depletion of uridine 5'-triphosphate and cytidine 5'-triphosphate provides an effective experimental chemotherapy with limited side effects. A clinical use of this new concept for the chemotherapy of hepatocellular carcinoma may serve as a useful approach.