Methods and apparatus for treatment of layered tissue defects such as a patent foramen ovale provide for applying energy to tissues adjacent to the PFO with a closure device that substantially closes the PFO. Apparatus generally includes an elongate flexible member having a proximal end and a distal end and an energy transmission member deployable from the elongate flexible member. The energy transmission member applies energy to the layered tissue defect at a first position and a second position adjacent to the first position so as to substantially close the layered tissue defect along at least a portion of the defect. Applied energy may be monopolar or bipolar radiofrequency energy or any other suitable energy, such as laser, microwave, ultrasound, resistive heating, direct heat energy, cryogenic or the like. PFO closure via energy-based approaches of the invention may help prevent stroke, treat migraine headache, and possibly treat or prevent other medical conditions.