The Barcelona forward's dismantling of Arsenal in the Champions League on Tuesday was the latest in a string of brilliant displays that have left pundits and fans scratching their heads for superlatives that can do justice to his talent.
Real will attempt to stop the 22-year-old La Liga top scorer in Saturday's "Clasico" at the Bernabeu, which is likely to go a long way toward deciding the battle between the leaders and champions Barca for Spain's domestic title.
Real top the standings on goal difference with eight matches left but after Saturday's clash head-to-head record will separate the arch rivals if they are still level on points and Barca have the advantage having won 1-0 at the Nou Camp.
Next up are Jose Mourinho's Inter, who face Barca in their two-legged Champions League semi-final later this month, before Messi lines up for Argentina in June in World Cup Group B with Nigeria, South Korea and Greece.
A big part of the problem for opposing coaches is that they do not know in what position Messi will be deployed and from what direction his twisting, darting runs will come.
Barca coach Pep Guardiola has been alternating between playing him wide on the right or in a more central role that allows him to drift into midfield and torment defenders with a mazy dribble that invariably ends in a shooting chance.
GUARDIOLA OBSESSION
One option, which carries a high level of risk, is to push up on Barca's defenders and attempt to break up as many attacks as possible before the ball reaches midfield orchestrators Xavi and Andres Iniesta or makes it through to Messi.
Many of Barca's goals come from moves started by goalkeeper Victor Valdes, with the ball flowing smoothly and quickly around the defence and midfield before Messi or one of his team mates in the forward line is released into space.
Guardiola is obsessed with making sure his back line have the skill and composure to carry or pass the ball out rather than sending a long pass that would likely result in possession handed to the other side.
But what to do once Messi inevitably does get the ball?
Damage limitation will probably be the most opponents can hope for and maximum concentration will be required.
Above all, players must avoid surrendering possession in their own half.
As a defender, there is little margin for error, as one slip or badly-timed lunge and the FIFA World Player of the Year, whose nickname is "the flea", will be away.
As sports daily reported on Wednesday that Real defender Alvaro Arbeloa would likely be deployed at left-back on Saturday and charged with repelling Messi's runs down the right flank, with support from midfielder Marcelo.
If Messi has a weakness, it is shooting with his right foot and Arbeloa would be wise to try to force him on to that side rather than allow him to carve an opening on his stronger left leg.
If he comes charging through the middle, midfielders Xabi Alonso and Gago or Lassana Diarra will be the first line of defence,
