Simple Summary: Molecular targeted therapy for cholangiocarcinoma (CCA) involves using drugs that specifically target molecules or pathways involved in molecular pathogenesis. In cholangiocarcinoma, specific mutations in different pathways occur more frequently than in other solid tumors; therefore, specific analysis is recommended early during the course of the disease. Targeted therapies in CCA aim to block the signals that promote cancer cell growth and survival, leading to tumor shrinkage and improved patient outcomes. However, targeted therapies may only be effective in a subset of patients with specific molecular alterations, highlighting the importance of molecular profiling to guide treatment decisions. Additionally, resistance to targeted therapies can develop over time, necessitating ongoing research into novel therapeutic strategies and combination approaches to improve treatment efficacy. We conducted a comprehensive review of the current literature of published data, clinical trials (MEDLINE; ncbi.pubmed.com), congress contributions (asco.org; esmo.org), and active recruiting clinical trains (clinicaltrial.gov) on targeted therapies in cholangiocarcinoma. Palliative treatment regimens were analyzed as well as preoperative and perioperative treatment options. We summarized the current knowledge for each mutation and molecular pathway that is or has been under clinical evaluation and discussed the results on the background of current treatment guidelines. We established and recommended targeted treatment options that already exist for second-line settings, including IDH-, BRAF-, and NTRK-mutated tumors, as well as for FGFR2 fusion, HER2/neu-overexpression, and microsatellite instable tumors. Other options for targeted treatment include EGFR- or VEGF-dependent pathways, which are known to be overexpressed or dysregulated in this cancer type and are currently under clinical investigation. Targeted therapy in CCA is a hallmark of individualized medicine as these therapies aim to specifically block pathways that promote cancer cell growth and survival, leading to tumor shrinkage and improved patient outcomes based on the molecular profile of the tumor. [ABSTRACT FROM AUTHOR]