The Brookline, MA native broke the Curse of the Bambino, leading the Red Sox to not one, but two World Series titles over his tenure with the team.
Now he'll try his hand at breaking the Curse of the Billy Goat.
While, overall, Epstein's time in office was successful, he did, nevertheless, make his share of bad decisions over his nine years in Boston.
Here are the 10 biggest mistakes Theo Epstein made with the Boston Red Sox.
Looking for a solution at shortstop, a position of shortcomings and frustration since Orlando Cabrera's brief but wonderful stint in 2004, Theo Epstein locked up Julio Lugo for four years at $36 million after the 2006 season.
Alex Gonzalez had been Boston's shortstop in 2006, playing superb defense, however Epstein was looking for more offense.
Lugo played three seasons before he was DFA'ed and traded to St. Louis in 2009. Over his time in Boston, Lugo batted .251 with a .319 OBP.
Some offensive threat, huh?
Suffice it to say, Lugo never lived up to expectations. He had been a career .277 hitter (with a .340 OBP) prior to playing for the Red Sox. Lugo failed to ever hit 10 or some homers in a season with Boston, something he had done four times prior.
Gonzalez, meanwhile, signed with the Cincinnati Reds for three years at $14 million that offseason.
In a fitting twist in 2009, the Red Sox, after dealing away Lugo, picked up Alex Gonzalez in a waiver trade in August.
Not that Gonzalez was a prime option himself (he missed all of 2008), but he would have been a much cheaper and more productive option than Lugo.
Following the 2005 season, Epstein refused to offer a fourth year to Johnny Damon, who subsequently got four years at $52 million from the New York Yankees.
The Red Sox felt that Damon, then 32, was too old to stay healthy and productive as an everyday outfielder for the length of such a contract.
They instead traded with the Cleveland Indians for Coco Crisp.
Over the six seasons since he left Boston, Damon has made over 3,700 plate appearances, hitting .279 with a .355 OBP. Over that stretch, Damon's played 871 games, which translates to a 145 games-per-season average.
Damon slid over to left while in the Bronx, and he chiefly DHed for the Rays this season, however he's proved to be a reliable player well into his 30s—something which Theo obviously didn't think he could do.
Orlando Cabrera shined bright in Boston after being acquired from the Expos in the famous Nomar Garciaparra trade in 2004.
A free agent after the season, he was not pursued by the Red Sox. They instead turned the position over to the then-28-year-old Edgar Renteria, who signed for four years at $40 million.
Renteria appeared to be in the prime of his career. He had blossomed into a star in St. Louis, winning three Silver Sluggers and two Gold Gloves and earning three All-Star selections during his six-year tenure with the Cardinals.
Renteria batted only .288 in his first month with Boston, however he finished up 2005 with decent offensive numbers (.276 average, .335 OBP and 70 RBI).
Renteria, however, led the majors with a career-high 30 errors.
"Rent-a-Wreck," as he became known on Boston sports radio, was traded to the Atlanta Braves after 2006 for minor league third baseman Andy Marte and cash. (Marte was dealt to the Cleveland Indians later that winter as part of the Coco Crisp deal.)
Epstein gets a lot of flack for the J.D. Drew deal, however, compared to some of his more recent moves, J.D. doesn't actually look super bad.
Five years at $70 million? Can Carl Crawford's contract be renegotiated to these terms?
The chief knock against Drew is that the guy couldn't stay healthy.
His games-played totals from his five seasons in Boston: 140, 109, 137, 139 and 81.
When he was healthy, Drew's numbers were, by and large, pretty good. From 2007 through 2009, Drew hit .276/.390/.485/.875. He also always played a sharp right field.
The true verdict is still out on the Carl Crawford deal, one year into Crawford's seven-year, $142 million deal.
Crawford was the big-ticket free agent last winter, and Epstein pushed hard to get him. He had a hard time convincing ownership that Crawford was not only worth it but also a good fit in the Boston lineup, as the Boston Globe's Bob Hohler writes.
Did Epstein feel pressure from Yankees GM Brian Cashman, who told ESPN New York's Ian O'Conner he faked interest solely to drive up Crawford's value?
Regardless, Epstein dropped a ton of cash on Crawford, the player who really stands to be his lasting legacy in Boston.
Only time will prove if Crawford ends up being remotely close to worth his massive contract.
Four years at $68 million! That's $17 million a year!
Yup, that's the extension that the Red Sox granted Josh Beckett back in April 2010.
At the time Beckett, 31, was a month away from turning 30.
He was coming off a 2009 in which he made 32 starts with a 3.86 ERA and 1.19 WHIP.
Good stuff, yes. But great stuff?
After an ugly and injury-plagued 2010, Beckett appeared back on track this season. However, a 2011 with strong season numbers will forever be marred by his own September failures as the team as a whole crumbled, and reports linking him to the now-infamous beer-laden clubhouse carousing.
While one can pile on the latest ill developments to an argument against Epstein granting Beckett a contract extension, the case is really much simpler than that:
Beckett's too old to be making the kind of money he's making. Done.
The scenario that led to the departure of Terry Francona, spin it whatever and whichever way, ultimately comes back to a failure by Epstein.
Tito certainly didn't play his best hand this past September, but the guy has an enormous track record of success in Boston—enormous!
Granted, Francona has often been put into positions to succeed behind the hard work and gobs of money running through the Boston front office.
That said, Francona, far more often than not, found terrific success with the teams he was given.
Peter Gammons has a nose for the truth: he said on Sept. 22 that he sensed a "growing disconnect" between Epstein and Francona.
If the Red Sox front office were really behind Francona, they would have extended his contract this summer.
The Red Sox have dropped a lot of money on Daisuke Matsuzaka since signing him in Dec. 2006.
A $51.1 posting fee. A six-year, $52 million contract.
To date, Dice-K has cost the Red Sox $92.8 million. He's owed a base salary of $10 million in 2012.
His shortcomings and failures have been documented at length. He's missed loads of time with a myriad of injuries and ailments.
Lauded as a workhorse at his signing, Dice-K has only once exceeded 200 innings (2007) and has only one season in which his ERA has been below 4.00 (2.90 in 2008).
One could even argue that Dice-K's ineptitude has led to a fundamental change in how MLB teams evaluate and approach signing Japanese players. Since Boston signed Matsuzaka, no Japanese player has come even close to getting the kind of contract that he did.
Theo signed Big John to the Sox in Dec. 2009. The results have been awful.
It's one thing to be bad (5.26 ERA and 1.50 WHIP over past two seasons). It's one thing to be expensive (five years at $82.5 million).
Pun and dark irony fully intended.
It's a good bet that Lackey is done in Boston. The Red Sox will likely eat a huge chunk of his contract and trade him to an NL team this winter.
The biggest mistake that Theo Epstein has made with the Red Sox, is his choice to leave them.
The Red Sox won two World Series during his tenure, but those are achievements that will largely be associated with those year's players and the now departed Terry Francona.
Epstein's legacy is far more mixed. He's leaving a mess behind him as he leaves Fenway for Wrigley.
Theo will be remembered for his gutsy trading of Nomar and his wooing of Curt Schilling. He'll be remembered as the guy who drafted Dustin Pedroia and Jacoby Ellsbury.
But he'll also be the guy linked to a litany of poor free-agency decisions.
Did any one tell Theo that the Cubs are plain terrible? He's going to have his work cut out for him in Chicago.
If the local boy really wanted to do good, he would not have left. And certainly not now.
As it is, few are complaining that he's gone.