Cholangiocarcinoma (CCA) is a rare but aggressive malignancy with a poor prognosis. For advanced disease, the standard therapeutic options are limited to systemic chemotherapy with gemcitabine and cisplatin, which have suboptimal outcomes. There is no established second-line systemic therapy and emerging new therapies are being developed. Targeted therapies inhibiting epidermal growth factor receptor, vascular endothelial growth factor, human epidermal growth factor receptor 2, and others are broadly tested in CCA. Unfortunately, they have not shown much clinically meaningful benefits over the standard care of chemotherapy. Early clinical trials of therapies targeting novel genomic alterations such as fibroblast growth factor receptor 2 fusion and IDH1/2 mutations are in progress and show promising results. Immunotherapy, especially immune checkpoint inhibitors, holds great promise. Clinical trials of immune checkpoint inhibitors, cytokines, adoptive cell therapy, and vaccines in patients with CCA are in progress. Herein, we review the current status of pharmacological therapy of advanced CCA.