A surgical instrument is disclosed. The surgical instrument may include at least one drive system that is configured to generate control motions upon actuation thereof At least one drive system defines an actuation axis. The surgical instrument may further include at least one interchangeable shaft assembly that is configured to be removably coupled to the at least one drive system in a direction that is substantially transverse to the actuation axis and transmit the control motions from the at least one drive system to a surgical end effector operably coupled thereto. A lockout assembly may interface with the at least one drive system for preventing actuation of the drive system unless the at least one interchangeable shaft assembly has been operably coupled to the at least one drive system.