Case rankled the Democratic establishment by challenging Akaka in 2006, bringing up the senator's age in the contest. Inouye and others in the establishment played a major role in Akaka's victory over Case, and ever since, lingering tension between Inouye and Case has been evident.
In 2010, Case ran in the special election contest for the Congressional seat of now-Gov. Neil Abercrombie (D). But Inouye and Akaka backed another Democrat in the race -- now-Rep. Colleen Hanabusa (D), even as some national Democrats viewed Case as the candidate Democrats should coalesce around. Hanabusa and Case split the Democratic base, allowing Republican Charles Djou to win the seat, only to lose it to Hanabusa in the November general election. Case said he doesn't think "there is any question" that Hanabusa would not be the current representative had Inouye not endorsed her.
Case, meanwhile, sees some key differences between 2012 and 2006.
"One obvious difference between the Senate election in 2012 and my candidacy in 2006 is there won't be an incumbent," said Case. "Starting early is definitely an advantage. In some of my past campaigns, I simply started too close to the wire," he added.
"I have run many campaigns over the course of my career and certainly Hawaii has changed politically from 10 or 20 years ago. I think like many parts of the country it tends toward a more moderate political philosophy. And not as purely tied to party as it once was. It is primarily, and in our values, more oriented toward the Democratic party, but that does not in any way mean that it will simply elect a Democrat because that's the label."
But Hawaii remains one of the nation's most Democratic states, and just elected Abercrombie, who had a liberal voting record in Congress, as governor.
With the state's favorite son -- President Obama -- at the top of the ballot in 2012, Democrats are due to get an extra boost, making it very difficult for the GOP to pick up the seat.
Republicans, meanwhile are holding out hope that they can land a top recruit. All eyes are on former Gov. Linda Lingle (R), who said in November that she would take six months off before deciding whether to run. Djou is another possibility, though he signaled that he will defer to Lingle.
Case said the threat of a Lingle candidacy should be taken seriously by Democrats.
"Democrats should be afraid of Gov. Lingle," said Case. "I have told national Democratic figures as well as folks here in Hawaii that they underestimate Gov. Lingle's candidacy at their great peril."
Case characterized his relationship with Akaka as "good." He noted that he reached out to Akaka the last couple of weeks as he honed in on his decision, but was not able to meet with him.
"It was extremely difficult decision to run against him in 2006. It was heartwrenching," Case said.
Updated at 3:56 p.m.