Lee began his career as a clerk for the U.S. District Court for the District of Utah before clerking for Samuel Alito, who was then a judge on the Third Circuit Court of Appeals. From 2002 to 2005, Lee was an assistant United States attorney for the District of Utah. He joined the administration of Utah Governor Jon Huntsman, serving as the general counsel in the governor's office from 2005 to 2006. Lee again clerked for Alito after he was appointed to the U.S. Supreme Court.
In 2010, during the Tea Party movement, Lee entered the party caucus process to challenge incumbent three-term Republican senator Bob Bennett. He promised that, if elected, he would serve no more than two terms. He defeated Bennett and business owner Tim Bridgewater during the nominating process at the Utah Republican Party convention. Lee won the Republican primary, and defeated Democratic nominee Sam Granato in the general election. He was reelected in 2016 and became the dean of Utah's congressional delegation when Representative Rob Bishop retired in January 2021. He was reelected again in 2022. Lee chaired the Joint Economic Committee from 2019 to 2021. He coordinated with and supported the Trump administration in its efforts to overturn the 2020 presidential election, but ultimately voted to certify the election.
Lee was born in Mesa, Arizona on June 4, 1971, the son of Janet (née Griffin) and Rex E. Lee, who was solicitor general under President Ronald Reagan. Lee's older brother Thomas Rex Lee is a justice of the Utah Supreme Court.

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