I tend to play one centre back who is quicker and has good anticipation as a covering defender, the other set to stopper. An ideal example is Vidic and Rio, Vidic as the battling, ball winning defender going in for all the headers, and Rio as the covering ball playing defender sweeping loose balls that get through. I play with Spurs so usually have Bassong and Dawson. Bassong as cover and Dawson as stopper. This works most of the time, but there are still going to be games where it doesn't work as well. Then you need to start looking at stopping certain players. If there's an attacking midfielder that causing your defence problems get your holding midfielder to man mark him. This usually works for me. I remember a game against Man City, Tevez was playing as a roaming forward and my defence didn't know what to do with him. He scored 2 goals in the first half pulling my defence all over the place. I then got Palacios to man mark him and then Tevez hardly got a touch the rest of the game. I wish I'd done it earlier!
Also, a lot of people don't seem to use the opposition instructions, but I do. If they are playing with one striker set it to tight marking, closing down and hard tackling. If they are playing 2 strikers start with both set to tight marking, then if one striker is causing more of a problem to your defence set him on closing down as well. You can check before the game starts to see which striker has the highest work rate.