Find which zone/look you want to base out of.
@bluejay13 uses a lot of 2 high stuff, I use a lot of 1 high, etc. If you're going to run something other than a 3-3-5, your front should correspond with your zone call. So if you're going to base out of Cover 2, you want to base out of 4-3 Stack, 4-2-5 Over, or 3-4 Over (or Odd). Cover 3, 4-3 Under, 4-2-5 Under, 3-4 Under (or Odd). If you're gonna run the 3-3-5, they're all odd fronts with the exception of 3-3-5 Bear and you can run virtually anything with an Odd front. Next, understand where the weak spots in those zones and where the "bubble" in the front is as well as gap responsibilities.
If you get this look, where is the best place to run the ball? In between the LT and LG, that's the "bubble." The weaknesses in zone you should know already because you're a good passer. Also think about the coverages when the defenders are off and when they're pressed. Cover 3 press, people are going to try to go over the top, so you need to have good DBs and carry the inside verticals with a LB or SS if they throw four verts at you. Off Cover 3, the first place people are going to attack is the outside with curls and deep outs, so you need to take those away, either manually or hot routing your flats to buzzes. Regardless, what Kirk says ad nauseum in the game is true. There are always going to be places to exploit, you just have to be aware of those areas and do your best to minimize them. Oh, and above all, you need talent, especially up front. The worst secondary in the world can still confuse people every once in a while if they're expecting Cover 3 and get 2 Man Under or something, but the worst defensive line in the world is asking to get run on 40-50 times a game in a game where the run is overpowered, which means you are probably going to lose.
You can user whoever, but most people prefer taking an LB or safety because you can user cover and try to cover up the holes in your zones. You can still user a lineman, though; bluejay did it/does it and gets good pressure. Or you can shift according to situation, like playing with an LB normally but shifting to a DE on 3rd and long to get a better pass and force a quicker throw or come up with a sack.