This invention provides minimally invasive mechanical instruments that are capable of laparoscopic or endoscopic approximation and fastening of soft tissues in a variety of interventional procedures. The devices of the present invention generally consist of a proximal handle assembly incorporating actuation means, an elongate tubular assembly (which may be flexible, rigid or combinations thereof) and a distal tool assembly incorporating mechanisms for engaging tissue at two or more spaced-apart locations on a tissue surface as well as mechanisms for deploying one or more tissue fasteners to securely hold the tissues in the approximated configuration. Typically the devices are provided in an initial collapsed (i.e. pre-deployed) configuration for insertion into the patient. After being deployed to an expanded configuration, tissue is contacted and engaged at two or more locations, and upon subsequent actuation by the user, at least one of the tissue engagement mechanisms, with tissue engaged, is repositioned by moving it toward another engaged tissue location, thereby approximating the engaged tissue locations near the distal end of the device. A variety of fasteners and fastener delivery mechanisms may be integrated into the devices of the present invention to securely and permanently hold the approximated tissues in the approximated configuration. Devices of the present invention provide surgeons the ability to carry out a variety of interventional procedures in which tissue approximation and fastening is required, in a safer and more efficient manner. Certain embodiments of the present invention enable entirely new minimally invasive tissue approximation and fastening procedures to be performed, such as closure of holes in the gastrointestinal lumen created to provide access to the abdominal cavity during natural orifice transluminal endoscopic surgery (NOTES) or laparoscopic plication gastroplasty procedures that reduce stomach volume from its external surface in the treatment of obesity.