Several studies have been recently published describing promising early results in genetic, epigenetic, and protein biomarkers from cyst fluid to help in both histologic diagnosis and detection of advanced neoplasia. The majority of studies have been completed using opportunistically collected archival cyst fluid and few report validation in independent sample sets. Results of ongoing multicenter prospective validation studies are awaited and will help define the best combination of cyst fluid molecular markers. In multifocal PCLs communicating with the pancreatic ductal system, a pancreatic juice biomarker is likely to be less invasive and more informative. Novel biomarkers in pancreatic juice and blood are in early phases of study. The field of molecular diagnostic biomarkers for PCLs is rapidly evolving with several promising candidate markers being prospectively evaluated. In the near future, these novel molecular markers, combined with advances in imaging technology, will transform clinical decision-making in the management of PCLs and improve patient outcomes.