It will be the 14th meeting between the two players, with Murray having the head-to-head advantage by eight wins to five, but few encounters have carried the same importance as the one taking place on Arthur Ashe Stadium later today.
It will represent the duo's fourth Grand Slam match, with both registering wins against each other at Flushing Meadows in the past, but with a semi-final spot at stake, the onus will be on to up the ante to secure a last-four tie with either Novak Djokovic or Mikhail Youzhny.
Since winning Wimbledon, Murray has failed to discover the scintillating form that has seen him win two major titles in the space of 12 months, with his continued participation in New York mainly down to his will to win, especially against second-round opponent Leonardo Mayer.
A general lull in his game was perhaps to be expected after his excursions at SW19, but while some believed that a second Grand Slam would lift a weight from his shoulders, it has almost added extra baggage for his first attempt at defending a major title.
Murray has shown flashes of brilliance on his way to the last eight, but he has also played lacklustre spells of tennis that would have been taken advantage of had he been playing a higher calibre of opponent.
The Scot has yet to meet anyone ranked inside the world's top 32, which could have mentally told him that he didn't require a top-level performance to progress, but he will have his hands full with Wawrinka should he not be focused from the first point.
The 28-year-old had been far from impressive ahead of the final Grand Slam of the year, but after having to overcome a tricky part of the draw, the world number 10 is playing some of the best tennis of his career.
Radek Stepanek, Ivo Karlovic, Marcos Baghdatis and Tomas Berdych have all been seen off for the loss of just two sets, and the confidence that Wawrinka has picked up over the past 10 days poses danger signs to the British number one.
Wawrinka has the game to beat any of the top players in the world, and his ability was proven during an epic five-set defeat at this year's Australian Open to Novak Djokovic, going down 12-10 in the decider.
The long-time Swiss number two employs an aggressive style of play against the bigger names, often taking sets off his opponents before failing to complete the job in the closing stages of the match.
He has met Murray on eight occasions on a hard court, allowing the Brit just one straight-sets triumph, while also picking up two wins in 2006 and 2010.
Under the watchful eye of coach Magnus Norman, he also dismantled Murray on the clay in Monaco earlier this year, allowing the 26-year-old just three games, which will surely only strengthen his mindset ahead of today's match.
Murray will rightly head into the encounter as the favourite, but it wouldn't necessarily be the biggest upset if Wawrinka did pull through against the two-time major winner.
The British number one will be expected to emerge with a win in four or five sets, but if Wawrinka finds his range from the baseline, the Arthur Ashe crowd could witness a US Open classic.