The payoff might be huge, but the risks are definately greater. The safest combo is a QB/RB pair since any QB/RB set that is worth having is not on a team that will be shut out of both phases of the game.
You have to play your best team every week. Kickers, DEF and TE do not count, so we are really only talking about QB/RB/WR. I do not like to do that, but against some teams (Bears, Cards, Lions, Bungles) it really can't hurt since you know that you will get your points.