De La Calle served in the cabinet as Interior Minister under two Presidents, Andrés Pastrana and César Gaviria.

[1] During his high school years, De La Calle was a known activist of Nadaism and an admirer of Colombian poet Gonzalo Arango.

For almost a decade De la Calle served in the Judicial Branch; he was appointed National Civil Registrar in the late 1980s during the administration of President Belisario Betancur.

De la Calle resigned as minister to pursue the presidency, but in the party primaries he was defeated by Ernesto Samper.

Afterwards he worked in his own law firm with his associates Ignacio Londoño Rivera, José Miguel de la Calle Restrepo and Mario Posada García-Peña.

[4] On 1 October 2012, President Juan Manuel Santos appointed De La Calle as the government's chief negotiator with the FARC in the Colombian peace process which was hosted in Havana, Cuba.

In March 2017, De La Calle announced that he will work to form a coalition of different political parties in order to provide a unified front that will protect and implement the peace agreements.

De La Calle hoped to prevent right wing candidate Iván Duque Márquez from getting elected and disrupting the Colombian peace process.