Difficulties in cholangiocarcinoma (CCA) management are largely due to the lack of specific biomarkers todiagnose CCA patients at an early stage. Most of CCA patients are diagnosed when the tumors have alreadyextensively invaded and/or metastasized, resulting in poor survival. Definite diagnosis for CCA is through ahistopathological study of e liver tissues, which is invasive to obtain the samples. The detection of CCA-associatedmarkers in patients’ sera seems to be a potential diagnostic approach, which is less invasive, inexpensive, anddoes not require a specialist to perform the diagnosis. To date, several serum markers, such as carcinoembryonicantigen, 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 singlemarker determination exhibits low sensitivity and specificity for diagnosis of CCA. Alternatively, multiple markeranalysis seems to have more optimistic prospects for improvement of diagnostic and prognostic determinationof CCA.