Surgeons face major challenges in achieving curative R0 resection for pancreatic cancers. When the lesion is localized, they must appropriately visualize the tumor, determine appropriate resection margins, and ensure complete tumor clearance. Real-time surgical navigation using fluorescence-guidance has enhanced the ability of surgeons to see the tumor and has the potential to assist in achieving more oncologically complete resections. When there is metastatic disease, fluorescence enhancement can help detect these lesions and prevent unnecessary and futile surgeries. Areas covered: This article reviews different approaches for delivery of a fluorescence signal, their pre-clinical and clinical developments for fluorescence guided surgery, the advantages/challenges of each, and their potential for advancements in the future. Expert commentary: A variety of molecular imaging techniques are available for delivering tumor-specific fluorescence signals. Significant advancements have been made in the past 10 years due to the large body of literature on targeted therapies and this has translated into rapid developments of tumor-specific probes.