Dubber just had a great post here on this subject that you need to read if you haven't already. He says, "In football terms, keeping a defense 'off rhythm' is the name of the game." He is correct. This post will focus solely on the Defensive End position and how to put the DE in conflict in order to keep him off-rhythm.
Urban Meyer talked about how much of what they did with their Spread offense at Florida was designed to control the DEs, because they are such tremendous athletes that they can take over a game by themselves. These freaks of nature can really wreak havoc on an offense if allowed to get into a rhythm. DEs that are strong and can run as fast as most RBs are a nightmare for an OT to try to block. An Offensive Coordinator must have plays designed to confuse and slow down the DE in order for the offense to have a chance and for his QB to survive.