Cholangiocarcinomas (CCA) are rare tumors of the liver with poor prognosis. The standard of care in patients with unresectable tumors or metastatic disease is combination chemotherapy (CT) with gemcitabine and cisplatin. Targeted therapies inhibiting EGFR, VEGF, MEK and others are broadly tested in CCA but to date, the existing data from randomized and nonrandomized trials do not justify the application of small molecules outside of clinical trials. In clinical practice, many patients receive second-line CT after failure of gemcitabine/cisplatin, although there is so far no evidence to support second-line CT. This review summarizes current chemotherapy protocols and ongoing studies, including conventional chemotherapy and targeted therapies.