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Sen. Joe Lieberman announced his retirement from the Senate on Wednesday, calling himself "a lucky guy," who will end a quarter-century career in Washington with no regrets.

"The reason I have decided not to run for re-election in 2012 is best expressed in the wise words from Ecclesiastes: 'To everything there is a season, and a time to every purpose under Heaven,'" said Lieberman, the 2000 Democratic vice presidential nominee who left his party to win a fourth term as an independent.

Surrounded by his large family and many admirers gathered in his hometown of Stamford, Conn., Lieberman credited President John F. Kennedy as his inspiration for political service.

"The politics of President Kennedy -- patriotic service to country, support of civil rights and social justice, pro-growth economic and tax policies, and a strong national defense-are still my politics," Lieberman said. "So maybe that means JFK wouldn't fit neatly into today's partisan political boxes either."

Lieberman, 69, entered the Senate in 1988 after a tough fight against incumbent Sen. Lowell Weicker, R-Conn. Shortly thereafter, he sought out Sen. John McCain, R-Ariz., with an interest in working in a bipartisan fashion, outside those "partisan political boxes." The two, now among the closest of friends, have done so many times over the years, particularly on issues of national security and foreign policy.

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"Along the way, I have not always fit comfortably into conventional political boxes-Democrat or Republican, liberal or conservative," Lieberman said. "I have always thought that my first responsibility is not to serve a political party but to serve my constituents, my state, and my country, and then to work across party lines to make sure good things get done for them."

It was a speech accented with bipartisan references, with the self-styled "Independent Democrat" making no direct reference to his turbulent tenure in the Democratic party, before he was forced out in 2006 when millionaire businessman Ned Lamont bested him in a Democratic primary. To win, Lieberman ran as an Independent, though he never officially changed his party registration.

Lieberman's estrangement from his party hit its zenith when he announced his support for McCain's 2008 presidential bid against then-Sen. Barack Obama, D-Ill. At the GOP nominating convention, Lieberman famously said to great applause, "Senator Barack Obama is a gifted and eloquent young man who I think can do great things for our country in the years ahead, but, my friends, eloquence is no substitute for a record, not in these tough times for America."

McCain's fondest memory of his friend of more than 20 years came in late 2007 when Lieberman announced that endorsement in New Hampshire. The independent senator told FOX News at the time, "There are some things more important than the political parties. One is friendship and the other is I think this guy is the best of all the candidates to unite our country and cross political lines so we can begin to finally solve some of the political problems that we have in this country and to lead us against the war versus Islamic elitist terrorism."

On Wednesday, McCain told Fox News in a phone interview, "It was a magical moment. I believe his endorsement was key in our winning independents."

All of this nearly cost Lieberman his chairmanship of a key committee, the Homeland Security and Governmental Affairs Committee, as liberals sought revenge for the perceived betrayal. Ironically, it was President Obama who stepped into the chasm and saved his onetime foe. Thereafter, Lieberman largely stuck with Democrats, though his opposition to a government-run insurance program further enflamed the left.

"He is a man of conscience. I look forward to working with him for the remainder of his term, and know we have many more accomplishments ahead," Sen. Susan Collins of Maine, top Republican on the security panel, said Wednesday. "We are all the better for his service in the U.S. Senate, and I will deeply miss him."

Many have speculated that Lieberman would, again, have faced a stiff challenge from the left and possibly even from the right. An independent in what would have surely been an expensive race might have face well-funded Republican and Democratic candidates.

To that, Lieberman replied, "I have never shied from a good fight, and I never will."

McCain said Lieberman, who was reportedly on his short list to be his vice presidential running mate, talked to his friend months ago about possibly leaving. The two recently "had a long conversation"on the subject.

"There's no doubt he had a tough fight ahead of him, but he's had tough fights before. I just think after 40 years, he's ready to do something else. Frankly, I'll miss him not only because of our deep and abiding friendship, but also because there are very few individuals with the knowledge to articulate the way Joe can," McCain said. "He's one of my dearest friends and I will miss him every day."

Lieberman, an expert on the Middle East and national security, said he intends to remain in public life, though he is not yet sure what he will do.

"When my Senate chapter draws to a close in 2013, I look forward to new opportunities that will allow me to continue to serve our country-and to stay engaged and involved in the causes that I have spent my career working on, and that I care so much about," he said.

With a toothy-grin and trademark quirky humor, Lieberman could not resist a joke in the moment, revealing to wife, Hadassah, the real reason he is leaving. "I promised you that when Regis leaves television, I'll leave the Senate! And here we are," Lieberman quipped, referencing his Greenwich neighbor and talk show host Regis Philbin, who announced his own retirement just this week. "Maybe we'll hang out more," he said with a laugh.

But Leiberman's mood was mostly reflective as he announced the end of his long career.

"This was not an easy decision for me to make because I have loved serving in the Senate and I feel good about what I have accomplished,"Lieberman said. "But I know it is the right decision and, I must say, I am excited about beginning a new chapter of life with new opportunities."