The focus will be on Patrice Evra of Manchester United and Luis Suarez of Liverpool when the arch-rivals clash in the Premier League at Old Trafford on Saturday (1245GMT).
It will be the pair's first meeting since Suarez racially abused Evra at Anfield in October, earning an eight-match suspension from which he returned to the Liverpool side as a substitute in Monday's 0-0 draw with Tottenham Hotspur.
Spurs, meanwhile, will go into their clash against fellow high-flyers Newcastle United at White Hart Lane on Saturday (1730 GMT) buoyed by the news that manager Harry Redknapp has been found not guilty of tax evasion charges.
He will delighted to be totally focused on the football as third-placed Spurs continue their unlikely challenge for the title and a more realistic one for a Champions League spot against their in-form opponents who are fifth.
Tensions at White Hart Lane will be nothing like those at Old Trafford where a delicate situation was exacerbated when Liverpool's pugnacious manager Kenny Dalglish said after the Spurs game that Suarez should never have been banned, despite Uruguayan admitting using the word "negro" in an on-field exchange with Evra during the 1-1 draw.
Saturday's match, featuring one of the fiercest rivalries in English football, is being shown live in more than 200 countries with an estimated global audience of about 900 million and while most of the attention will be on the match, the cameras will also closely follow the pre-match handshake.
The FA has said the handshake will go ahead at Old Trafford and Gordon Taylor, the chief executive of the Professional Football Association, said: "It is an opportunity for football to show it can deal with these issues, and everyone can learn and move on."
Manchester United manager Alex Ferguson said on Tuesday that football needed to take a hardline stance against racism which has begun to rear its head in the English game again after seemingly lying dormant for years.
Evra has not said if he will shake Suarez's hand, but whoever dominates on the pitch could hold the key to a victory that will either lift United above leaders Manchester City at the top of the table - at least until Sunday - or take Liverpool closer to the top four.
Liverpool beat United in the FA Cup fourth round on 10 days ago when Suarez was banned, but will find United in a defiant mood after they came back from a 3-0 deficit at Chelsea on Sunday to draw 3-3.
That lifted United on to 55 points, two behind City who travel to Aston Villa on Sunday (1600GMT).
City manager Roberto Mancini, who has been without Yaya and Kolo Toure on African Nations Cup duty, said it was important his side remained in first place until they returned.
"Next week we will have a difficult game at Villa, but if we have the same attitude that we had on Saturday we will do well. It is important that we stay top and don't think about the other teams," Mancini said.
Tottenham eked out a point from the goalless draw with Liverpool and Redknapp will be further cheered if Younes Kaboul, Jermain Defoe and Rafael van der Vaart return after injury against Newcastle United.
Chelsea, who are third on 43 points, and Arsenal, sixth on 40, travel north for tough matches at Everton and Sunderland respectively.
At the other end of the table, 19th-placed Blackburn Rovers, who lost 7-1 at Arsenal last week, take on fellow relegation candidates Queens Park Rangers, who are 16th but just three points better off.
Another relegation-haunted game takes place at the Reebok Stadium where 18th-placed Bolton Wanderers face rock bottom Wigan Athletic who increasingly look doomed after nine league matches without a win.
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