but there must be a setting that has ran amuck, because when the machine coordinates are not set at 0,0,0, along with work coordinates, when running a program, it will takeoff for the machine coordinates and not the work coordinates.
Are you using a CAD/CAM combination? Or maybe you are using a program from someone else?
In any event, it is clear that your program must have a G53 instruction near the start (as Gerry said). THIS is your problem. It is switching your machine from Work Coords to Machine Coords. Get rid of it! Nothing else is needed.
If you are using CAM, get rid of the G53 from the Post Processor.
Cheers
Roger