Described herein are drive systems and methods. One exemplary system includes a tool having a proximal handle and a catheter body. The tool can be mated with a rail and the rail mated with a frame. The connection between the tool and rail and/or the rail and frame can allow relative movement of the tool with respect to the frame, a patient, and/or a point of reference. In one exemplary configuration the handle of the tool rotates around an axis that corresponds to a portion of the catheter body, such that rotational movement of the handle has a minimal impact on longitudinal movement and/or position of a distal end of the tool.