The senator's family issued a statement saying he died Monday evening at National Naval Medical Center in Bethesda, Md. He had been receiving chemotherapy for acute myeloid leukemia.
Just before the 2006 election, Thomas was hospitalized with pneumonia and had to cancel his last campaign stops. He nonetheless won with 70 percent of the vote, monitoring the election from his hospital bed.
Two days after the election, Thomas announced that he had just been diagnosed with acute myeloid leukemia.
"He never complained," former Wyoming Senator Alan Simpson (who went to high school and college with Thomas and was a close friend) told CBS News correspondent Steve Kathan. "He fought right to the end. I saw him 2, 3 weeks ago in Washington at an event, there he was, 'Al, I'm doing fine, I'm coming along.'
"There's a phrase in the Indian community: 'My heart is on the ground.' And that's where it is right now," Simpson said.
President Bush, in Prague for a series of meetings with Czech leaders in advance of the G-8 summit, said he and the First Lady are "deeply saddened" at the death of the Wyoming lawmaker.
"Senator Thomas was a tireless and effective advocate for the people of his beloved home state. He was a man of character and integrity known for his devotion to the values he shared with the people of Wyoming," the president said. "He leaves a lasting legacy as a guardian of Wyoming's lands and resources and our country's National Parks."
Vice President Dick Chaney was "greatly saddened" by his passing, and said in a statement, "Craig was a public servant of the first rank: Honest, decent, and devoted to his constituents. During Craig's long career in office, the people of Wyoming counted on him to represent their interests with common sense and integrity. He never let us down, and even in a time of serious illness Craig was faithful to his duties in the United States Senate."
Wyoming Gov. Dave Freudenthal, a Democrat, will appoint a successor from one of three finalists chosen by the state Republican Party, who will serve until the next general election, in November 2008.
Thomas was a low-key lawmaker who reliably represented the interests of his conservative state, often becoming involved in public lands issues. He worked in behind-the-scenes posts to oversee national parks, including Yellowstone in Wyoming.
He was also an advocate for domestic energy and minerals production. He worked to protect Wyoming's mining industry from foreign competition and backed efforts to get a federally-funded coal gasification plant built in the state.
After his first round of chemotherapy, Thomas returned to the Senate in December, a month earlier than expected. A few months later, he said he felt better than he had in a long time. But he returned to the hospital for a second round of chemotherapy in May.
"I'm resolved to do all I can to keep the leukemia in check," he said then. "I've been feeling very good over the last several months — even returning to my regular morning run. But I've always known that further treatments are common and could periodically be part of this thing."
"Wyoming had no greater advocate, taxpayers had no greater watchdog, and rural America had no greater defender than Craig Thomas," Senate Republican Leader Mitch McConnell said Monday night. "The Senate is a lesser place without Craig here, but the state of Wyoming and our nation are much better places because he was here."
Thomas entered Congress in a special House election in 1989 to replace Dick Cheney when the future vice president was named defense secretary by the first President Bush. Thomas won that race with 52 percent of the vote.
In 1994, Thomas won his first Senate race by beating former Gov. Mike Sullivan 59 percent to 39 percent. Thomas was re-elected by a wide margin in 2000, winning 74 percent of the vote against Democrat Mel Logan and Libertarian Margaret Dawson.
Thomas had previously served five years in the Wyoming Legislature.
He was born in Cody, Wyo., and was raised on a ranch. He graduated from the University of Wyoming with a degree in agriculture, then served four years in the U.S. Marines.
He also was vice president of the Wyoming Farm Bureau and general manager of the Wyoming Rural Electric Association.
Thomas' wife, Susan, and three of their four children, were by his side when he died Monday night, according to a statement issued by the family, which thanked well-wishers for their prayers.