Establishing a tissue diagnosis in patients with suspected pancreaticobiliary malignancies remains challenging. Endoscopic retrograde cholangiopancreatography (ERCP)-based sampling methods have been reviewed in a previous issue of this journal but, unfortunately, the diagnostic yield continues to be inadequate in a significant minority of patients. The availability and image quality of cholangioscopy and pancreatoscopy have advanced in the last few years and our ability to make a diagnosis on imaging alone is improving. However, a definitive diagnosis requires tissue; cholangiopancreatoscopy allows targeted biopsies of the epithelium of the biliary and pancreatic ducts. This article reviews the evidence that cholangioscopy- and pancreatoscopy-guided biopsies improves diagnostic yield over ERCP-based tissue sampling techniques.