Hepatocellular carcinoma (HCC) is generally difficult to treat. This is primarily due to the reduced liver function of most patients and the low sensitivity of liver cancer cells to chemotherapy. This has been demonstrated in many clinical trials. Molecular therapies might represent an improvement in the systemic treatment of patients with HCC. In addition to anti-angiogenic drugs, compounds which interfere with specific signal transduction cascades have shown promising results in smaller trials. There are only limited numbers of studies about the systemic treatment options for biliary cancers. To date, the best response rates have been achieved with combination chemotherapies containing platinum analogues and gemcitabine. In the absence of larger clinical phase III trials, no standard chemotherapy for biliary cancers exists today.