The most common malignant causes of biliary strictures are pancreatic cancer and cholangiocarcinoma. Differentiating between malignant and benign causes of biliary strictures has remained a clinical challenge. Endoscopic retrograde cholangiopancreatography (ERCP) remains the mainstay and first-line method of tissue diagnosis but has a poor diagnostic yield. This article reviews the causes of biliary strictures, the initial clinical evaluation of biliary obstruction, the diagnostic yield of ERCP-based sampling methods, the role of newer tools in the armamentarium for evaluating strictures, and ways to address the ongoing challenge of stricture evaluation in patients with primary sclerosing cholangitis.