NOTES remains one of the hottest topics in both gastrointestinal surgery and gastroenterology communities. There is now clinical data demonstrating that basic NOTES procedures in humans are feasible. We believe that at this point NOTES is ready to carefully move from the laboratory to human trials to identify where NOTES approaches might be beneficial and where they are not. In this very magistral lecture, Prof. David Rattner explains which are the unsolved questions of NOTES and what progress is made to move to standard human applications.