Methods and apparatus are provided for diagnosing and treating digestive or other organs (as well as other parts of the body) endoluminally and transluminally, via instruments passed into the GI tract per-orally and/or per-anally. The instruments may, for example, pass transluminally out of the stomach and/or the colon through a breach formed therein in order to conduct diagnostic or therapeutic procedures, such as gastroenterostomy.