In 1916 the Cubs moved into Weeghman Park (opened 1914), which in 1926 was renamed Wrigley Field and is today the second oldest baseball stadium still in use (Boston's Fenway Park opened in 1912). During the 1910s and '20s the team enjoyed limited success, winning NL titles in 1910 and 1918. From 1929 to 1938 the Cubs dominated the NL, winning four pennants (1929, 1932, 1935, and 1938) behind the strong play of centre fielder Hack Wilson, catcher Gabby Hartnett, and second baseman Rogers Hornsby (Hornsby, Rogers). The 1932 World Series produced one of baseball's legendary moments—Babe Ruth (Ruth, Babe)'s “called shot,” when the New York Yankees slugger allegedly pointed to centre field and promptly hit a home run to that very spot.

After the 1938 season the Cubs had only one winning year until 1945, when they won the NL pennant. That year's World Series launched what has become known as the “Curse of the Billy Goat” (versions of the story vary). In the fourth game of the World Series, tavern owner Billy Sianis was forced to leave Wrigley Field after showing up with his goat; upon his ejection, Sianis cursed the franchise. Since 1945 the Cubs have failed to return to the World Series.

Post-1945 Cubs history is distinguished primarily by disappointment on an epic scale. In 1969 the Cubs were first in their division (then the NL Eastern Division) throughout most of the season, leading it by as many as eight and a half games in mid-August before collapsing at the end of the season and falling to eight games behind the New York Mets, who went on to win the World Series. In 1984 the Cubs looked set to break their World Series drought, but, with the Cubs leading in the fifth and decisive game of the National League Championship Series (NLCS) against the San Diego Padres, a ground ball went through first baseman Leon Durham's legs, helping the Padres defeat the Cubs. In 2003 the Cubs again appeared to be headed for a World Series, leading three games to two over the Florida Marlins in the NLCS. Five outs away from making it to the World Series, the Cubs missed the chance at another out when fan interference blocked an attempted catch by outfielder Moises Alou of a pop foul near the stands (the so-called Bartman incident). The Cubs ended up losing the game—and the series. Despite these disappointments, in 2008 the Cubs became only the second team in major league baseball history to record 10,000 wins. The Cubs won their second straight NL Central Division title in 2008, marking the first time in 100 years that the team qualified for the play-offs in two consecutive seasons.

The Cubs franchise has produced numerous Hall of Famers, including the double-play combination of shortstop Joe Tinker (1902–12, 1916), second baseman Johnny Evers (1902–13), and first baseman Frank Chance (1898–1912). Other notable Hall of Famers are infielder Ernie Banks (Banks, Ernie) (“Mr. Cub”), who spent his entire career (1953–71) with the team, hitting 512 home runs; outfielder Billy Williams (1959–74); second baseman Ryne Sandberg (1982–94, 1996–97); and pitcher Ferguson (“Fergie”) Jenkins (Jenkins, Fergie) (1966–73, 1982–83). Ron Santo, the team's third baseman from 1960 to 1973, is among the most popular Cubs players not inducted into the Hall of Fame.