A torn right ACL cost Lee his senior year at Penn State and he partially tore his left ACL in 2009, which is the only reason the Cowboys could grab a guy with his talent -- 10th on their board -- in the second round.
A hamstring injury cost Lee two games as a rookie in 2010. A dislocated wrist made him miss a game in 2011 and forced him to play much of the year with a cast.
Toe surgery took him off the field for 10 games in 2012, and a strained hamstring and sprained neck forced him to miss a total of five games last season.
Now, we can add another injury to the list. This one concerns his left knee.
We just don't know how bad it is yet. An MRI scheduled for Tuesday afternoon will reveal the actual damage, but a source has told ESPN that the Cowboys fear Lee has a torn ACL.
Brace for the worst based on coach Jason Garrett's description of the play.
"It looked like he had overrun the play a little bit and was trying to put his foot in the ground and come back," said Garrett, "but I don't want to say that definitively because I just haven't seen the tape."
Head trainer Jim Maurer and associate trainer and rehab specialist Britt Brown helped Lee off the field -- he put no weight on his left leg -- after attending to him for a few minutes.
Profanity flowed from Lee's mouth as he was helped past the media and into the training room.
The frustration had to be overwhelming for a player who in January vowed to explore every possible way to stay on the field for 16 games this season. He's missed 15 of the team's past 32 games.
"Sean's been as committed and hardworking a teammate as I've ever been around," Tony Romo said. "I love the guy like a brother. He's the epitome of what you want in a football player. You always know Sean's going to give you 100 percent.
"Any time you can get as many of him as you can on a football team, you've got a great chance."
This isn't Lee's fault. It's not strength and conditioning coach Mike Woicik's fault. It's not Garrett's fault or Zack Martin's fault, either, since he engaged Lee on the play.
It's just bad luck.
These aren't injuries associated with poor training or conditioning. They're injuries that sometimes occur in this brutal game.
That said, none of us should be surprised Lee is hurt again. Lee hasn't played a 16-game season in any of his first four NFL seasons.
The Cowboys certainly shouldn't be surprised.
Heck, they spent a fourth-round pick on Iowa linebacker Anthony Hitchens earlier this month to be Lee's backup. That's a premium pick to use on a player expected to be a backup. But with Lee's injury history, it made some sense.
"He really does everything he can to get himself ready to play. Unfortunately, he had to deal with a few of those things, but he's as mentally tough as an individual I've ever been around," Garrett said. "Whatever the circumstances are, he always puts his best foot forward and strives to be his best. I don't anticipate this being any different."
When the Cowboys signed Lee to a six-year, $41 million deal, it included clauses that tied his money to his health. He can make an additional $9 million over the life of the contract if he's on the field for 80 percent of the team's plays.
The real disappointment is that Lee is such a good player, when he's healthy.
He's a dynamic player capable of changing a game in an instant. He did it against the New York Giants in the 2012 opener.
The score was tied 0-0, but the Giants were driving for a touchdown. Lee sprinted right, slithered between two New York linemen and launched himself at Giants running back David Wilson, who fumbled.
The Cowboys recovered the fumble, and it was among their biggest defensive plays in their 24-17 upset win.
What about his 52-yard interception return against San Diego last season? Oh, he also had a career-high 18 tackles in that game.
You could go on and on about the plays he's made.
His 9.2 tackles per game the past two seasons rank fifth in the NFL. No linebacker has more than the 11 interceptions Lee has accumulated the past three seasons, which is why he's a perfect fit in this defense.
The 4-3 Tampa 2 scheme requires the middle linebacker to make deep drops in zone coverage.
Both moves were painful but smart.
With Ware and Hatcher gone, this was Lee's defense without equivocation. Now, it appears that the NFL's worst defense must move forward without its best player.