Patients with unresectable cholangiocarcinoma (CCA) face a poor prognosis, and there are few effective treatment options for the disease. The standard of care for patients with locally advanced or metastatic CCA is chemotherapy with a gemcitabine-based doublet. Unfortunately, the clinical benefit obtained with these regimens is modest, with a median overall survival of about one year. For CCA that is chemotherapy-refractory or recurs after first-line chemotherapy, the treatment options are even more limited, and no relevant randomized controlled data are available. In recent years, molecular profiling has shed light on the molecular basis of CCA and identified subgroups of patients that might benefit from a personalized treatment approach. These efforts resulted in the recent FDA approval of the fibroblast growth factor receptor (FGFR) inhibitor, pemigatinib, as a second-line treatment for patients with advanced CCA harboring an FGFR2-fusion or rearrangement. Several other targeted agents also are under evaluation in patients with CCA, of which the isocitrate dehydrogenase inhibitor has had the most promising results. Finally, immunotherapy is being explored as a new treatment approach for advanced CCA patients; indeed, the immune checkpoint inhibitor pembrolizumab can already be used to treat CCAs that are mismatch repair deficient. This review is a comprehensive overview of the treatment options for CCA and offers a glimpse into what the future could hold for these patients.