Abstract: Instruments, systems and methods are provided for performing submucosal medical procedures in a desired area of the digestive tract using endoscopy. Instruments include safe access needle injection instruments incorporating electrosurgical capability, a submucosal tunneling instrument, a submucosal dissection instrument, a mucosal resection device and submucosal biopsy system. Systems include a combination of one or more of such instruments with or without injectable agents. Embodiments of various methods for performing the procedures are also provided.