Klitschko defeated WBO Heavyweight Champion Sultan Ibragimov at Madison Square Garden in New York City on 23 February 2008 to unify the IBF and WBO heavyweight titles. The Klitschko-Ibragimov fight was the first heavyweight unification since Holyfield-Lewis in 1999.

On 12 July 2008, at the Color Line Arena in Hamburg, Klitschko defeated Tony Thompson by eleventh round knockout.

Klitschko was scheduled to defend his titles against Alexander Povetkin later in 2008,[2] but on 25 October, Povetkin withdrew from the fight due to an ankle injury. Instead, Klitschko faced Hasim Rahman on 13 December 2008 and won by TKO. This was the third time Klitschko fought at the SAP Arena in Mannheim, Germany. He dominated the fight, winning every round while making good use of his left jab. The referee finally called a stop to the contest in the 7th round after Rahman failed to respond to a series of good shots.

The brothers have been quoted saying that it is only a matter of time until they unify the WBA title belt which is currently held by David Haye. If they achieve this feat, the Klitschko brothers will become the first brothers in heavyweight boxing history to simultaneously hold all of the belts.

On 20 June 2009, Klitschko retained the IBF, WBO, IBO world heavyweight titles and also won the vacant Ring Magazine heavyweight title by defeating Ruslan Chagaev when Chagaev retired after an onslaught of punches towards the end of the ninth round. As Chagaev was WBA champion in recess, the title was not on the line.

On 9 December 2009, Klitschko's management group, K2 Promotions confirmed that a bout with Eddie Chambers has been agreed to take place in Germany on March 20 2010. This mandatory title defense, originally scheduled for December 2009 had to be delayed due to a hand injury that Klitschko sustained in training that required surgery.