A surgical instrument with a tissue-clamping end effector, where actuation of the instrument is locked out when the thickness of the tissue clamped in the end effector is not within a specified thickness range. The end effector may comprise a tissue thickness module that senses the thickness of the tissue clamped in the end effector. The surgical instrument also comprises a control circuit in communication with the tissue thickness module. The control circuit prevents actuation of a working portion of the end effector when the thickness of the tissue clamped in the end effector is not within the specified thickness range.