Biliary strictures frequently present a diagnostic challenge during pre-operative evaluation to determine their benign or malignant nature. A variety of benign conditions, such as primary sclerosing cholangitis (PSC) and IgG4-related sclerosing cholangitis, frequently mimic malignancies. In addition, PSC and other chronic biliary diseases increase the risk of cholangiocarcinoma and so require ongoing vigilance. Although traditional methods of evaluation including imaging, detection of circulating tumour markers, and sampling by endoscopic ultrasound and endoscopic retrograde cholangiopancreatography have a high specificity, they suffer from low sensitivity. Currently, up to 20% of biliary strictures remain indeterminate after pre-operative evaluation and necessitate surgical intervention for a definitive diagnosis. The discovery of novel biomarkers, new imaging modalities and advanced endoscopic techniques suggests that a multimodality approach might lead to better diagnostic accuracy.