Simple SummaryEndoscopic modalities have a central role in the diagnosis of pancreato-biliary cancers. Endoscopic ultrasound (EUS) is crucial in the diagnosis of both solid and cystic pancreatic lesions through tissue acquisition and fluid sampling. Intraductal brushings and biopsies performed during endoscopic retrograde cholangiopancreatography (ERCP) can provide diagnosis for biliary strictures, and additionally, cholangioscopy can allow direct visualization and image-directed biopsies. Moreover, advances in molecular markers can increase diagnostic accuracy and assist in risk stratification for premalignant lesions, such as pancreatic cystic lesions. The present review focuses on recent developments in the field of endoscopic modalities for the exploration of pancreato-biliary malignant and premalignant lesions.AbstractPancreatic cancer and cholangiocarcinoma are life threatening oncological conditions with poor prognosis and outcome. Pancreatic cystic lesions are considered precursors of pancreatic cancer as some of them have the potential to progress to malignancy. Therefore, accurate identification and classification of these lesions is important to prevent the development of invasive cancer. In the biliary tract, the accurate characterization of biliary strictures is essential for providing appropriate management and avoiding unnecessary surgery. Techniques have been developed to improve the diagnosis, risk stratification, and management of pancreato-biliary lesions. Endoscopic ultrasound (EUS) and associated techniques, such as elastography, contrasted-enhanced EUS, and EUS-guided needle confocal laser endomicroscopy, may improve diagnostic accuracy. In addition, intraductal techniques applied during endoscopic retrograde cholangiopancreatography (ERCP), such as new generation cholangioscopy and in vivo cellular evaluation through probe-based confocal laser endomicroscopy, can increase the diagnostic yield in characterizing indeterminate biliary strictures. Both EUS-guided and intraductal approaches can provide the possibility for tissue sampling with new tools, such as needles, biopsies forceps, and brushes. At the molecular level, novel biomarkers have been explored that provide new insights into diagnosis, risk stratification, and management of these lesions.