Described is a full-thickness resection system which includes a control unit coupled to a proximal end of a flexible endoscope. The control unit remains outside of a body when the stapling head is in an operative position within a body lumen. The control unit includes (i) an anvil actuator coupled to an anvil in the stapling head, actuation of the anvil actuator moves the anvil axially relative to a stapling mechanism in the stapling head to compress a folded full-thickness portion of lumenal tissue between the anvil and the stapling mechanism. In addition, the control unit includes (ii) a stapler actuator coupled to the stapling mechanism in the stapling head, actuation of the stapler actuator causing the stapling mechanism to drive staples through the folded lumenal tissue against the anvil. Also, the control unit includes (iii) a tissue cutter actuator coupled to a tissue cutter in the stapling head, actuation of the tissue cutter actuator causing the tissue cutter to resect portions of the folded lumenal tissue.