Minimally invasive procedures performed through percutaneous, endoscopic, and endovascular access routes have changed the management of a variety of malignancies. Natural orifice transluminal endoscopic surgery (NOTES) is a novel access route to the peritoneal and thoracic cavities utilizing transvisceral incisions and flexible endoscopes to perform surgical procedures. NOTES appears to be feasible and preliminary clinical experience with NOTES is accumulating rapidly. Although few studies have described the use of NOTES in the oncologic setting, based on published data in humans and swine, it seems that NOTES has potential applications in cancer patients including diagnostic peritoneoscopy, thoracoscopy and mediastinoscopy, lymph node resection, gastro-jejunostomy, solid organ resection, and intestinal resection. In spite of this potential, there are currently few data to support the superiority or even equivalence of NOTES to current surgical therapy. Additional data and clinical experience with NOTES will be required before definite conclusions can be drawn regarding future applications of NOTES in oncology.