She received her diploma in 1963 in Saint-Maurice and a licence degree in political science at the Graduate Institute of International Studies, Geneva, in 1968.

From 1981 to 1997 Calmy-Rey served as a representative in the Grand Conseil of the canton of Geneva as a member of the Social Democratic Party (PSS/SPS), and was president of the assembly during 1992–1993.

Calmy-Rey supports Switzerland joining the European Union and she is an Eminent Member of the Sergio Vieira de Mello Foundation.

[3] Since 2016, Calmy-Rey has been a member of the board of the Global Leadership Foundation (chaired by Helen Clark), an organisation that works to support democratic leadership, prevent and resolve conflict through mediation and promote good governance in the form of democratic institutions, open markets, human rights and the rule of law.

[4][5] On 1 January 2007, Calmy-Rey became the second female president of the Confederation in history, the first having been her predecessor on the Federal Council, Ruth Dreifuss.

[6] From 2012 to 2013, Calmy-Rey was a member of the High-Level Advisory Council of the President of the 67th Session of the United Nations General Assembly, Serbia's then foreign minister Vuk Jeremić.

[9] In February 2020, Calmy-Rey joined around fifty former European prime ministers and foreign ministers in signing an open letter published by British newspaper The Guardian to condemn U.S. President Donald Trump’s Middle East peace plan, saying it would create an apartheid-like situation in occupied Palestinian territory.

[11][12] According to the BBC, Calmy-Rey was "widely criticised" for putting on a headscarf to meet Iranian President Mahmoud Ahmadinejad on 19 March 2008, even though it was acknowledged that she was simply following proper social protocol.

[25] Calmy-Rey also prompted controversy by attending the signing of a multibillion-dollar natural gas deal of a Swiss energy supply company with Iran.