With Ensign's exit, Heller, Nevada's former secretary of state, could emerge as the front-runner, Duffy said.
"He held statewide office for 12 years," she said. "Unlike many members of Congress, he is pretty well known statewide."
Heller said he and his wife wish Ensign the best.
"This must have been a very difficult decision for John to make," he said.
Ensign's announcement did not dampen criticism from the watchdog group Citizens for Responsibility and Ethics in Washington. The organization called for the Senate Ethics Committee to continue its investigation and not use the announcement as a reason to drop it.
"Unless and until Sen. Ensign resigns, the investigation should proceed full-steam ahead," said Melanie Sloan, the group's executive director.
Ensign's decision sent shockwaves through Nevada's political circles, with some leaders expressing an interest in the open seat.
"Today is a day when all Nevadans should be grateful to Senator Ensign for his consistent and conservative votes in the United States Senate," Krolicki said, adding that he and his family are considering their options.
Berkley said Ensign's announcement was not unexpected.
"I am not surprised," she said. "I think John could have gone either way. I know up until a couple of weeks ago, I spoke to him, and he told me he was definitely running for election."
Berkley said the announcement will likely allow Republicans to rally around a front-runner and avoid a nasty primary. She said she is still weighing her options.
"I am taking my time with this decision," Berkley said.
Once elected with 55 percent of the vote, Ensign's admission that he cheated on his wife seemingly marked the beginning of his political downfall.
In just two terms, he had gained a foothold in the GOP's Senate leadership and had been discussed as a potential presidential candidate.
"If there was ever anything that I could take back in my life, this would be it," Ensign said at the time. "I violated the vows of my marriage."
Amid the scandal, Ensign's parents provided the Hamptons with $96,000 that the parents described as a gift. Ensign also helped find Doug Hampton a lobbying job.
The Justice Department and the Federal Election Commission investigated then dropped the cases with little explanation.
The Senate ethics panel, however, recently named a special counsel to look into the matter.
Freking reported from Washington.
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