At the state party conference in March 2006, Rösler was elected as chairman of the Lower Saxon FDP with 96.4% of the votes; he succeeded Walter Hirche, who had decided to step down after twelve years at the helm.

Following the 2009 national elections, Rösler succeeded Ulla Schmidt as Federal Minister of Health in Angela Merkel's second cabinet.

[16] In January 2011, he asked German pharmaceutical companies to refrain from delivering anesthetic sodium thiopental to the US, a request they agreed to.

[17] Rösler succeeded Rainer Brüderle as Federal Minister of Economics and Technology on 12 May 2011 and Guido Westerwelle as Chairman of the FDP on 13 May 2011 and was also instated as Vice-Chancellor of Germany on 16 May 2011.

[18][19] On 7 June 2011, Rösler attended the state dinner hosted by President Barack Obama in honor of Chancellor Angela Merkel at the White House.

The leadership decided that he would remain but not lead the party in the federal elections, instead acting in a team with Rainer Brüderle as top candidate.

In January 2014, Rösler became a member of the managing board and Head of the Centre for Regional Strategies of the World Economic Forum (WEF) in Switzerland, under the leadership of chairman Klaus Schwab.

[23] From late 2017 until early 2019, Rösler served as chief executive officer of New York-based Hainan Cihang Charity Foundation Inc., the largest shareholder of HNA Group.

[24][25] In 2020, Rösler founded Consessor AG, a consulting firm based in Zug which advises companies on strategic management and internationalization.