The Argentine has repeatedly demonstrated his fight and resolve over the years, and he has realistic aspirations of upsetting the world No 3's hopes of a 20th major.
Roger Federer should be wary of 2009 repeat when he faces Juan Martin del Potro in US Open quarter-finals
It was eight years ago when Roger Federer last stood on the verge of winning three grand slam tournaments in a calendar year.
The Swiss player had already won the French Open and Wimbledon, and had navigated his way through to the 2009 US Open final where standing in his way was Argentine player Juan Martin del Potro.
Federer had been strong favourite to win a 17th career grand slam, but Del Potro, then aged 20, had shown remarkable nerve and poise, in what was his first major final, to come from a set down twice before winning 3-6, 7-6, 4-6, 7-6, 6-2.
Del Potro looked like a superstar on that night in New York and it looked as if he had arrived as a serious player at the top of the game.
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But, the 2009 US Open remains Del Potro's sole appearance in a the final of a major as injury problems have wrecked much of his career since then.
A wrist injury, which required surgery in 2010, broke up his momentum, and though he got himself back up and competing and was up to No 4 in the world by January 2014, the spot he had been in before his physical issues began four years earlier, more problems were ahead.
Multiple surgeries on a second wrist injury meant he missed most of 2014 and 2015 and was outside the top 1,000 in the ATP rankings by the time he made his comeback in early 2016.
The highlight of Del Potro's return was beating then world No 1 Novak Djokovic and Rafael Nadal on his way to taking the silver medal at the Rio Olympics, and then leading Argentina to their first Davis Cup success in November.
It was a reminder of the talent that Del Potro has, and the heart and belief he has demonstrated throughout his career, from having the nerve to beat the best player in the world in your first appearance in a grand slam final, to having the drive to return to the upper echelons of the game from a career threatening injury.
This had been a quieter year thus far for Del Potro. He had started the year at No 38 in the world and entered the US Open ranked No 28, with a run to the quarter-finals at the Rome Masters the high point.
But, the flashes of the old Del Potro have resurfaced in New York in his run to the quarter-finals and a date with Federer on Wednesday.
He had looked doomed against sixth seed Dominic Thiem in the fourth round on Monday, losing the first two sets 6-1, 6-2.
But he fought back, surviving two match points, to win the next three sets 6-1, 7-6, 6-4.
Understandably, given they have never met at the US Open before, there is a lot of focus on the fact that if Federer wins, and Nadal beats Andrey Rublev in his quarter-final, they will meet in the semi-finals on Friday.
Federer, however, will not be looking beyond Del Potro, who he will know is a dangerous threat to his hopes of a 20th grand slam crown.
Del Potro is not the player he was eight years, but the power in his groundstrokes remains there and his spirit is as dogged as ever, as Thiem will attest.
Federer has overcome his bumpy start to the tournament when he went to five sets in his opening two matches, and while not firing on all cylinders, he was far too good for Philipp Kohlschreiber on Monday in the fourth round.
Federer should be too strong for Del Potro, especially if he can find the form that saw him not drop a set on the way to winning Wimbledon for an eighth time in July.
It has been nine years since the last of Federer's five US Open crowns came his way and, especially with the way the bottom half of the draw has opened, he will not have much better chances, at the age of 36, of winning that sixth Flushing Meadows title.
Del Potro, and in all probability Nadal, still stand in his way, but if he maintains the play that accounted for Kohlschreiber in straight sets then he should be on one side of the net when the men's final takes place on Sunday.
Del Potro stopped him once before, and it will not be for lack of effort and passion, if the Argentine comes up short this time around.