From 1971 to 1975, he was a student at the Pontifical North American College in Rome and studied theology at the Pontifical Gregorian University. In 1979, he obtained a licentiate and in 1987 a Doctorate in sacramental theology at the Catholic University of America in Washington, D.C.

Appointed bishop of Rapid City, South Dakota, on 7 July 1998, he received episcopal ordination on the following 21 September. On 30 June 2010, he was appointed by Pope Benedict XVI as Bishop of Spokane, Washington, and took canonical possession of the diocese the following 3 September. On 20 September 2014, Pope Francis appointed him as metropolitan archbishop of Chicago, where he began his ministry on 18 November of the same year.

He was chairman of the USCCB Committee for the Protection of Children and Young People (2008-2011) and of the National Catholic Educational Association Board (from 2006-2008) and is a member of numerous committees of the Conference of Catholic Bishops of the United States of America. He is a member of the Congregation for Bishops, the department of the Roman Curia that oversees the selection of most new bishops.

Created and proclaimed Cardinal by Pope Francis in the consistory of 19 November 2016, the titular church of San Bartolomeo all’Isola.