Lionel Messi is possibly the best player in the world, on possibly the best team in the world. He plays center forward, and is expected to drop deep off the opposing central defenders in an attempt to find the ball as frequently as possible. Anyone who plays this role -- especially for a team as good as Barcelona -- is going to get to see a lot of the ball. Preventing Messi from receiving the ball simply isn't possible, but it is possible to keep the ball from going to him directly, and in immediately dangerous positions.
This is where Real Madrid midfielder Sami Khedira comes in. His fitness issues and slight drop-off in form have been as big of a contributor to Real Madrid's early season struggles as anything else during their campaign, but he appears to be finally back to full fitness.
When fully fit, Khedira's energy, tenacity and quickness are virtually unmatched. His positioning is also very solid, and he's technically strong enough to start a counter-attack when he wins the ball back from the opposition deep in midfield. He's much more of a box-to-box midfield player than a true defensive midfielder, but his role generally changes a bit against Barcelona. While Jose Mourinho's sides have opted to play with Barcelona in recent Clasicos, rather than sitting deep and just stifling them, Khedira still needs to play more conservatively against Barcelona than he does against other opponents.
Messi will give the Madrid central defenders plenty to think about on Wednesday, but they should simply be the team's last line of defense, not their primary defense against Messi. Madrid's success or lack thereof is likely to depend on how effective Khedira is at shutting down simple passing lanes to Messi, forcing Andres Iniesta and Xavi Hernandez to pass sideways. He'll also need to make interceptions and start counters. If he's not shutting off passing lanes to Barcelona and starting counters for Madrid, the Clasico could be a walk in the park for the Blaugrana.