Step one is normally to go into a zone defense. I find that a 3-4 defense with a LB in QB Spy works well. The LB will hang around the line until the QB hands off, then go after the RB. It also helps a ton if the QB is a running QB and/or runs the option. The Cover 2 works well because the two CBs in short zone will normally chop down runs to the outside, while the LBs take care of runs on the inside.
Of course, it helps a lot if you are good at taking user control of a LB or safety. But I normally take control of the DT or a DE and try to bust through the line and force the RB to take a different route which gives the rest of the D time to collapse on him.
Depending on the type rushing attack, the 5-2 and 1-5-5 can also be useful against the run.