Oklavol,
The spread offense can succeed, with various caveats.
1) Wide receivers cannot get lazy with their blocking. A lot of running from the spread seems to end up further outside than it was designed to, and the wide receivers need to block every play
2) If there is a strong passing attack, defenses have a tendency to overcommit one way or another...usually (if they're in a 4-3-4 personnel set) they'll run an outside linebacker out to cover a receiver, which creates mismatches if the passing is strong. If that comes to pass, a lot of DCs will want to walk a safety over the top of the OLB and CB (creating a triangle on the defense over twin receivers). This leaves the middle of the field shorthanded for either passing or running.
3) If the running is strong, the safeties will usually adjust by coming up to aid in run support. This prevents them from being able to play deep zones and leaves them vulnerable to a play action that attacks the empty zones where a cover 2 or Tampa 2 would normally be set up.
4) If the offense is balanced, the defense plays back on their heels and need to gamble in order to make up for the disadvantage that being tenuous is. The beauty of a gambling defense (i.e. Ole Miss during their 10-win 2003 season) is that if they guess right there's no one who can score on them. If they guess wrong, it's a quick 7 points. That leads to...
5) Offensive discipline. It seems like small things, but my opinion is that a defense should never be able to line up and have any clue what kind of play the offense will run. I've had good success at the high school level by looking closely to see what certain players do on certain plays, and it only takes one guy getting undisciplined to blow up a play. A spread offense from the shotgun is vulnerable to the halfback tipping plays (this happens a LOT more than anyone would ever let on). But we once had a field day against a very highly-regarded offense because I picked up on something that the left guard was doing on certain plays in his stance....a very, VERY minor thing to spot, but we shut out a nationally-ranked offense.
6) Chemistry. Every coach and player wants to talk about chemistry, but a spread can run into trouble if guys get into a freewheeling mode. For the double option that Texas ran to death last year, it required very strict discipline on the part of the offensive line to not only drive their men one way, but then to completely shift directions when the defense keyed (since they can see what the OL can't) Vince Young whenever he'd pull the ball. Quickly changing on the fly like that is not an easy task, and the OL is the unit that needs to become the most cohesive.
The beauty of the spread is that what can be run from it is limitless. The downside is that it's an inherently tricky setup to master, and against an offense that audibles a lot, the defense can play the same game by rotating, shifting, or stemming. Of course, that can all be disrupted by the offense going on a quick count, but being in the shotgun negates that advantage as well.