In 2013, the Houston Astros will move to the American League, making two leagues with an odd number of teams (15) for the first time in major-league history.
This will require changes in the way schedules are created, because that alignment will require at least one interleague series to be played at all times during the season.
ESPN.com's Jayson Stark has a summary of the sorts of changes that will occur.
Stark writes that interleague play will have each division play teams in an "assigned" division from the other league each season, on a rotating basis. Technically, that's the way things are done now, but with unequal numbers of teams in each division, there are some "outlier" series. With all divisions having five teams, it'll be easier to schedule this. There will be either 18 or 20 interleague games. Regarding the "rivalry" games (e.g. Yankees/Mets, Cubs/White Sox, Dodgers/Angels):
It's now going to be mandatory that each team have some sort of interleague rival. But a few teams will rotate rivals. In the AL East/NL East, the Red Sox and Blue Jays will "share" rivalries with the Braves and Phillies. In the AL West/NL West, the Rangers and Astros will "share" rivalries with the Diamondbacks and Rockies. And elsewhere, you'll get Pirates-Tigers and Padres-Mariners every darned year -- for now anyway.
Finally, Stark writes that one of the most important factors in revamping the schedule is to make it "balanced" -- in other words, every team plays essentially the same "strength of schedule". Some teams believe the current schedule is unfair in that respect, and makes it easier for certain teams to qualify for the playoffs.
As always, we await further developments.