This is a mouthful, I'll see how much I can get into. Theres SO much to discuss.
Ok, first and foremost, it depends on the scheme. Let's consider the 4-3 scheme for simplicity sake, because the 3-4 can get very complicated.
First you look at the dline. The dline is a good indication of what you expect as far as pass rush. If everyone is one gapping, chances are youre only getting front 4 pressure. If someone is 2 gapping, depending on when and where, there could be a blitz.
Theres 2 ways of deciphering this. First, you use motions to see if its man coverage or zone. 2nd, you mix up your count to see who jumps early out of the LB position. That let's you know where the blitz is coming from, and what kind of blitz it is. Also, the stance of the LBs is an indication. If theyre in a rushing stance, chances are theyre blitzing. If theyre in a 2 point stance, theyre more likely in coverage.
Now, the secondary. You need to see how far the safeties are playing. Observe the coverage by the CBs, if its bump and run, etc. Again, use motion to see if its man or zone.
After the hike, the first thing you do is read the defense. You should know your routes, and by reading the defense, you'll know instantly which route to hit because each defensive scheme is vulnerable to something, so by reading the defense properly you can make your hot read quickly and get the ball to that person. Its not about hitting the open man, its about hitting the right wndow. No one is open in the NFL for more than 1 second, you gotta hit them at the right time. And you usually do that by reading the defense.
Now, also, remember, you can't just read the defense and hit the target. Defenses are too fast and will pick you off. You have to trick defenders in coverage. So you have to look off defenders and sell the play one way while going the other way.
Thats a basic overview. Of course it can get much more complex, but thats the basics of it. Its not an easy position to play.
Of course, its not as simple as Ive said. Zone defense can be very complex, and defenses do a very good job disguising their coverage. Alot of times they line up in man and drop into zones etc. So motioning isn't always an accurate indication.
I can get real detailed but its far too complex of a topic. So much changes during the play, its nothing like Madden.