But veteran Johnny Damon has been through those trials and tribulations, coming to the conclusion that for the most part, baseball is baseball.
"It's a little different," Damon said. "We have a few pitchers that can hit pretty well. The games normally go a little bit quicker. There's more strategy."
Trying to hit pitching you don't normally see on a regular basis is perhaps the greatest task.
"It's always tough," Damon said. "We don't know much about their team, but we still have to go out and play our best baseball, and hopefully it's good enough to win a couple of games here."
Preparation from the dugout is somewhat different as well.
"I obviously like it better when it's on the American League side, so that I can use my DH," Indians manager Manny Acta said. "I do like Interleague. I like seeing players that otherwise we wouldn't be able to see.
"The challenge is being able to trust the advance scout and the video work that you do," he said. "It's such a short series that even if you get the right information, a guy can go off."