Traditional flexible endoscopy has been limited to the confines of the gastrointestinal lumen; however, recent developments involving translumenal access to intra-abdominal structures hold the potential to revolutionize flexible endoscopy. Over the past few years various studies have detailed techniques that intentionally breach the lumen and provide endoscopic access to the peritoneal cavity for diagnostic and therapeutic procedures. Unlike standard surgical approaches, which require incisions to be made in the abdominal wall, natural orifice translumenal endoscopic surgeryTM (NOTESTM) avoids the need for abdominal incisions and can offer specific advantages to select patient populations. Animal models have been used to demonstrate the possible applications of NOTES, including transgastric peritoneoscopy, tubal ligation, gastrojejunostomy, partial hysterectomy, oophorectomy, and transcolonic exploration, liver biopsy and cholecystectomy. In this Review, we highlight important advances in NOTES since it was first described and analyze the hazards and potential benefits associated with this innovative approach.