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Patients with indeterminate biliary stricture frequently pose a challenge in the clinical management. Discrimination between benign and malignant biliary strictures is important to prevent the morbidity and mortality associated with incorrect diagnoses. Traditional tissue sampling using endoscopic retrograde cholangiography does not always produce a definitive diagnosis, with a considerable proportion of cases remaining as indeterminate biliary strictures. Recent advances in endoscopic and molecular techniques have the potential to improve the diagnostic and prognostic accuracy of biliary strictures. This article reviews various etiologies of biliary strictures and discusses the recent advances of diagnostic approaches for indeterminate biliary tract obstruction.