Cholangiocarcinoma (CCA) encompasses a heterogeneous collection of malignancies for which diagnostic biomarkers are lacking and population screening is otherwise infeasible due its status as a rare disease. Coupled with high post-surgical recurrence rates among the minority of patients diagnosed at resectable stages, systemic clinical management will inevitably be required for the majority of CCA patients with recurrent and advanced disease. In this review, we discuss the therapeutic potential of different classes of molecular targets at various stages of development in CCA, including those targeted at the tumor epithelia (oncogenic, developmental, metabolic, epigenomic) and the tumor microenvironment (angiogenesis, checkpoint regulation). Further, we discuss the successes and failures of CCA targeted therapies, emphasizing key lessons learned that should pave the way for future molecular target evaluation in this uncommon yet bona fide target-rich disease.