Difficulties in cholangiocarcinoma (CCA) management are largely due to the lack of specific biomarkers to diagnose CCA patients at an early stage. Most of CCA patients are diagnosed when the tumors have already extensively invaded and/or metastasized, resulting in poor survival. Definite diagnosis for CCA is through a histopathological study of e liver tissues, which is invasive to obtain the samples. The detection of CCA-associated markers in patients' sera seems to be a potential diagnostic approach, which is less invasive, inexpensive, and does not require a specialist to perform the diagnosis. To date, several serum markers, such as carcinoembryonic antigen, carbohydrate antigen (CA) 19-9, CA242, CCA-associated carbohydrate antigen, mucin glycoproteins, cytokines, etc., have been reported to be the potent diagnostic and prognostic markers for CCA. However, a single marker determination exhibits low sensitivity and specificity for diagnosis of CCA. Alternatively, multiple marker analysis seems to have more optimistic prospects for improvement of diagnostic and prognostic determination of CCA.