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Background/Aims Endoscopic visualization of the microscopic anatomy can facilitate the real-time diagnosis of pancreatobiliary disorders and provide guidance for treatment. This study aimed to review the technique, image classification, and diagnostic performance of confocal laser endomicroscopy (CLE). Methods We conducted a systematic review of CLE in pancreatic and biliary ducts of humans, and have provided a narrative of the technique, image classification, diagnostic performance, ongoing research, and limitations. Results Probe-based CLE differentiates malignant from benign biliary strictures (sensitivity, ≥89%; specificity, ≥61%). Needle-based CLE differentiates mucinous from non-mucinous pancreatic cysts (sensitivity, 59%; specificity, ≥94%) and identifies dysplasia. Pancreatitis may develop in 2-7% of pancreatic cyst cases. Needle-based CLE has potential applications in adenocarcinoma, neuroendocrine tumors, and pancreatitis (chronic or autoimmune). Costs, catheter lifespan, endoscopist training, and interobserver variability are challenges for routine utilization. Conclusions CLE reveals microscopic pancreatobiliary system anatomy with adequate specificity and sensitivity. Reducing costs and simplifying image interpretation will promote utilization by advanced endoscopists.