That changed in April, when Labor Commissioner Michael Thurmond announced he would leave the post he had held for more than a decade to challenge Isakson for his Senate seat.
Thurmond is seen as a formidable challenger, one of a few black candidates elected statewide and well-liked among many Georgians. To challenge Isakson, Thurmond will have to win the Democratic primary July 20.
If he defeats Isakson in November, Thurmond would be the first black senator elected in Georgia and the first elected in the South since Reconstruction.
Thurmond's opponent in the primary is Conyers resident R.J. Hadley, who has little name recognition and not much money. Isakson, on the other hand, has more than $6 million for his re-election bid.
Political observers say Isakson is the favorite in November, but if anyone can beat him, they say, it's Thurmond.
"Johnny Isakson is a pretty popular incumbent in a Republican state," said Kennesaw State University political science professor Kerwin Swint. "That's the position you'd want to be in. He did draw a pretty well-qualified opponent. But everything Isakson has going for him is an obstacle for Michael Thurmond."
Isakson is seen by some as vulnerable -- not only because he has drawn strong opposition, but also because his health has become an issue.
He was hospitalized earlier this year for an irregular heartbeat and a blood clot. Doctors detected the irregular heartbeat during an exam after an earlier hospitalization for a bacterial infection.
Afterward, the 65-year-old claimed a full recovery as he launched into his re-election campaign. Thurmond, 57, maintains Isakson's health did not factor into his decision to run.
Isakson's long career in Georgia politics, during which he built a reputation as a moderate, has made him popular in the state. He sailed into office with nearly 60 percent of the vote in 2004, when Georgians also overwhelmingly helped re-elect George W. Bush to his second term as president.
Thurmond has said the Senate appeals to him because it presents a unique opportunity to bring his expertise as the state's job czar to the economic recovery for Georgia and the nation.
Emory University political science professor Michael Leo Owens said Thurmond's reputation as a cautious politician suggests he sees the seat as winnable or that he might be able to help others in the Democratic Party.
"It might be that he sees himself trying to help Roy Barnes get re-elected as governor," Owens said. "Even if he loses, I think just having the presence of Michael Thurmond, who has a great reputation, on the ballot will turn out a good number of African-Americans. And they'll vote for Barnes."
The black vote is seen as key to this year's elections, though race is not seen as a major factor in the contest. Thurmond has downplayed the issue in previous statewide campaigns. Hadley, his opponent in the primary, also is black.
Hadley, who worked on Barack Obama's presidential campaign in 2008, is hoping Georgia voters are ready for more change.
"I think voters are ready for a new face, a new approach to the challenges that we have in our state," he said. Political observers say Hadley, who spent his childhood in New Jersey and graduated from Dartmouth College, will need to introduce himself to Georgia voters.