Simonet served as mayor of Anderlecht from 2000 until his death and as Minister-President of the Brussels-Capital Region from 15 July 1999 to 18 October 2000. He served as state secretary for European Affairs of Belgium from 12 July 2003 until 12 February 2004 when he became Minister-President of Brussels for the second time on the resignation of Daniel Ducarme following revelations of Ducarme's unpaid taxes in the newspaper L'Avenir . He led the MR list in the elections of June 2004, losing to the Socialists led by former Minister-President Charles Picqué and gave up the minister-presidency a month later.
Simonet was hospitalised on 9 September 2006 as the result of a pulmonary embolism.[2] In the elections which followed on 8 October 2006 he was re-elected as mayor of Anderlecht with 8500 preference votes. On 14 June 2007 he suddenly died of a heart attack aged only 43.[3][4][5][6]