Experience with EUS guided fine-needle-aspiration of pancreatic tumors has demonstrated that regardless of size and location, most lesions in the pancreas are readily accessible by this technique. This has lead to the development of EUS guided placement of fiducials into pancreatic tumors to facilitate radiotherapy as well as injection of antitumor agents into cystic and solid pancreatic lesions. We review the technique for placing fiducials under EUS guidance into solid pancreatic neoplasms. To reduce risk of postprocedure pancreatitis, we recommend that no more than 3 fiducials be placed at a time, and that this procedure not be combined with fine-needle-aspiration for acquisition of tissue. We describe initial experience with TNFerade™, a replication deficient adenovirus vector that contains cDNA encoding for tumor necrosis factor, for treatment of adenocarcinoma of the pancreas. Finally, we review the current status of ethanol and a combination of ethanol and paclitaxel for ablation of pancreatic cysts.