Iniesta will reach the landmark tonight when he lines up against La Liga rivals Atletico Madrid in the Champions League quarter-final second leg tie between the two clubs at the Vincente Calderon Stadium.
The midfielder, who was outstanding in the first leg during last week's 1-1 draw, will forever be remembered for scoring the winning goal in the 2010 World Cup final as Spain defeated Holland 1-0 to lift the Jules Rimet trophy for the first time.
As career highs go, it does not get any better than that. But while starring in his country's most successful period in its history, he has also been a leading light for his club during a trophy-laden spell for the Catalans.
Since making his Barcelona debut on October 29, 2002 Iniesta has helped the club win 17 trophies, including six La Liga titles and three European Cups.
Here are five memorable moments from along the way, illustrating that Iniesta really is the man for the big occasion.
Chelsea, May 2009
Following a goalless draw at the Nou Camp, Barcelona are 1-0 down to Chelsea in the Champions League semi-final and heading for heartbreak with 90 minutes on the clock.
But this first-time strike from Iniesta deep into injury-time gave them a priceless away goal and turned the tie on its head, capping an impressive performance from the Spaniard in the process. The Catalans went on to beat Manchester United in the final in Rome later that month.
Manchester United, May 2011
Iniesta at his imperious best. The understanding with central midfield partner Xavi that night at Wembley was almost telepathic as Barcelona beat Manchester United 3-1 in the Champions League final.
After the game Sir Alex Ferguson admited his side had been given `a hiding` and said, `in my time as a manager, it's the best team I've faced.`
Real Mallorca, March 2012
A telling sign of his influence and importance, Iniesta made his 51st successive La Liga appearance without being on the losing side.
It broke the previous record set by Real Madrid legend Emillio Butragueno as a 2-0 win saw Barcelona close the gap on their bitter rivals at the top of the table.
AC Milan, April 2012
Barcelona lead 2-1 at the Nou Camp in the Champions League quarter-final second leg but another goal for AC Milan would see the Italians go through on away goals.
Iniesta relieves the pressure and gives his team a two-goal cushion with this superb touch and finish. At the end of the season he was named UEFA Player of the Year for his performances throughout the tournament.
Real Madrid, March 2014
This emphatic finish set Barcelona on their way to a thrilling 4-3 victory over their rivals, keeping them firmly in the La Liga title race.
The precise importance of the goal remains unknown but if the Catalans go on to win the league this season they will certainly look back at this game as key moment.
Iniesta has only scored 50 goals in the 499 matches he has played prior to tonight. He might not get many, but the one's he does score carry some significance.
Barcelona will be hoping he is on target against Atletico Madrid as the team have never lost when he has found the back of the net.