On offense, I have two fourth down rules and another rule to help prevent safeties.
On defense I have a rule for each offensive personnel grouping. When I am really active I take the time analyze my opponent's play usage for certain groupings. Then I either edit and activate the rule for that grouping or I deactivate it if it appears balanced and I let the matrix I setup dictate what we do on defense.
My setup normally works pretty well, but I also have pretty solid teams and am still a bit of a noob, so take my advice with a grain of salt.
Also, if you really want to get detailed, you could download the game logs and figure out what they use in certain personnel groupings in certain downs and distances in certain areas of the field and make a bunch of rules based on that. I plan on doing this some day but haven't had time to workout the spreadsheet formulas I would need.