Clinical implementation and widespread application of natural orifice translumenal surgery (NOTES) has been limited by the lack of specialized endoscopic equipment, which has prevented the ability to perform complex procedures including colorectal resections. Relative to other types of translumenal access, transanal NOTES using transanal endoscopic microsurgery (TEM) provides a stable platform for endolumenal and direct translu menal access to the peritoneal cavity, and specifically to the colon and rectum. Completely NOTES transanal rectosigmoid resection using TEM, with or without transgastric endoscopic assistance, was demonstrated to be feasible and safe in a swine survival model. The same technique was successfully replicated in human cadavers using commercially available TEM, with end oscopic and laparoscopic instrumentation. This approach also permitted complete rectal mobilization with total mesorectal excision to be performed completely tra nsanally. As in the swine model, transgastric and/or transanal endoscopic assistance extended the length of proximal colon mobilized and overcame some of the difficulties with TEM dissection including limited end oscopic visualization and maladapted instrumentation. This extensive laboratory experience with NOTES tra nsanal rectosigmoid resection served as the basis for the first human NOTES transanal rectal cancer excision using TEM and laparoscopic assistance. Based on this early clinical experience, NOTES transanal approach using TEM holds significant promise as a safe and substantially less morbid alternative to conventional colorectal resection in the management of benign and malignant colorectal diseases. Careful patient selection and substantial impr ovement in NOTES instrumentation are critical to optimize this approach prior to widespread clinical application, and may ultimately permit completely NOTES transanal colorectal resection.