Lofton was a six-time All-Star (1994–1999), four-time Gold Glove Award winner (1993–1996), and at retirement, was ranked 15th among all-time stolen-base leaders with 622.

During his professional baseball career, Lofton's single-season stolen-base count led the American League (AL) on five occasions and all of MLB three times.

For the Wildcats, Lofton was the backup point guard (to Craig McMillan and Steve Kerr) on a team that made it to the Final Four of the 1988 NCAA Division I men's basketball tournament.

[4] Lofton earned a degree in studio production at the University of Arizona while playing minor-league baseball for the Houston Astros.

In his major league debut with the Houston Astros on September 14, 1991, he went 3-for-4 with a double and scored three runs against the Cincinnati Reds.

[16] With Steve Finley already entrenched as Houston's centerfielder, Lofton was traded during the off season to the Cleveland Indians with Dave Rohde for catcher Eddie Taubensee and right-handed pitcher Willie Blair.

His season's stolen-base count, which led the AL, also broke a franchise record (previously set by Miguel Diloné in 1980).

[16] When the strike began in August, the Indians were in second place by one game in the AL Central to the Chicago White Sox.

In the eighth inning of game six, Lofton had an infield bunt, stole second base, and scored from second on a passed ball between pitcher Randy Johnson and catcher Dan Wilson.

[25] The Indians lost the World Series to the Braves in six games despite finishing the regular season with a major league-best 100–44 record in the strike-shortened year.

[26] The following season in 1996, the Indians again had the best record in baseball (99–62) and Lofton's stolen-base total (75) led MLB for the second time in four years.

[36] For the season, Lofton's .333 batting average and 27 stolen bases were team highs (his stolen-base total was to that point a career low).

Lofton, who was considered the "most sought-after free agent" following the 1997 season, returned to the AL and Cleveland Indians when he signed a three-year, $24 million contract.

"[42] In 1998, Lofton's batting average dropped to .282, but his 87 walks were a career high, and his 54 stolen bases were double his previous year's 27.

[16] The Indians won the AL Central with an 89–73 record and their match-up against the Boston Red Sox, three games to one, in the 1998 ALDS.

In the series against the Red Sox, Lofton's .375 batting average led the Indians, as did his two stolen bases and six hits.

[47] On September 3, 2000, in a 12–11 win over the Baltimore Orioles, Lofton tied an MLB record previously held by Red Rolfe when he scored in 18 consecutive games.

[48] He tied an Indians' franchise single-game record with five stolen bases and won the game with a 13th-inning walk-off home run.

[53] White Sox general manager Kenny Williams had stated when Lofton was healthy, like he was during the second half of the 2001 season, Chicago had obtained one of the best leadoff hitters in the game.

[16] On July 28, he was traded to the San Francisco Giants of the NL for minor leaguers Ryan Meaux and Félix Díaz.

In the ninth inning, Cardinals manager Tony La Russa summoned left-handed reliever Steve Kline to face Lofton, who had already notched two singles in the game.

Giants manager Dusty Baker considered bringing a right-handed hitter to pinch-hit for Lofton, but decided against doing so on the advice of his three-year-old son.

[56] Lofton hit a first-pitch single to the outfield, scoring David Bell from second base and creating a 2–1 Giants victory.

[57] With the Pirates, he hit .277 and stole 18 bases in 84 games before being traded to the Chicago Cubs, where he was reunited with manager Dusty Baker.

[62] Lofton's .323 against the Marlins led the Cubs' starting line-up, as did his 31 at-bats, and he had the team's only stolen base of the seven-game series.

In the 2004 ALCS against the Boston Red Sox, the Yankees had built a 2–0 series lead when Lofton stated, "My ultimate goal is for me to try to win a championship.

[75] The Jacobs Field crowd greeted Lofton with a standing ovation during his first at-bat for this tour of duty with the Indians.

"[76] In game one of the 2007 ALDS against the Yankees, he went 3-for-4 with four RBIs and one stolen base, which tied him with Rickey Henderson for MLB's all-time postseason stolen-base record (33).

[77] Lofton earned his 34th career postseason stolen base in game four of the 2007 ALCS, setting a new MLB record for playoff steals.

[86] Lofton falling off the BBWAA ballot after one year despite his career statistics, accolades, and relatively clean reputation during the steroid era has often been considered by baseball fans as one of the most egregious Hall of Fame exclusions in history, and has been used as an example of criticism towards the election process.