BACKGROUND: Natural orifice transluminal endoscopic surgery (NOTES) is currently of major research interest as it may offer significant clinical potential for endoscopic procedures in the future. Nevertheless, many issues are still unresolved. The aim of this study is a systematic review of the literature to evaluate techniques and technologies to address the issue of achieving a secure gastric wall defect closure. METHODS: Studies were identified by searching MEDLINE, EMBASE, Current Contents, Cochrane Library, Entrez PubMed and Clinical Trials Database until December 2008. We divided the different technologies into four groups: clipping, stitching, stapling and occluding systems. We analysed the different technologies in terms of (1) simplicity of manoeuvring for port closure, (2) security of introduction, (3) permanent implantation of the device into the organ, (4) effectiveness of port closure and (5) availability on the market. RESULTS: Twenty-eight published studies were identified, while nine clinical trials are ongoing. Among proposed technologies, staplers and occluders have greater effectiveness but lack of security, and in the case of staplers also lack of simplicity of use. None of the stitching technologies can really be considered effective except for the Flexible Endostitch, which on the other side is difficult to handle in the current fashion. Standard clips, although easy to handle, have never been proved to be reliable, as only mucosal layer closure has been demonstrated to date. On the other side, the over-the-scope clip is likely to be effective, secure to introduce and simple to handle within the hollow organ. CONCLUSIONS: Achieving reliable closure of the hollow organ defect represents the first step towards implementation of clinical NOTES. The current data do not yet allow definitive and clear advantages or disadvantages of the different options to be determined. The introduction of the EURONOTES registry will help us to understand in which direction to proceed.