For the first few years of interleague play, the Cubs played only teams in the AL Central. That changed in 2003, when interleague was opened up to all divisions. The Cubs hosted the Yankees that year for the first time since the 1938 World Series.
But the Red Sox didn’t come to Wrigley in ‘03, and so this meeting of the teams at Wrigley Field was the first one ever in the regular season. The Cubs and Red Sox played in the 1918 World Series, but Cubs home games that year were played in Comiskey Park, not in the relatively new Weeghman Park, later to be renamed Wrigley Field.