In 2007, Time magazine honored him as one of "America's 10 Best Senators," pointing to his legislative achievements and the help he provided in securing expanded funding for the National Institutes of Health.
A career moderate, as a Republican Specter had a long record of bucking his party even while in leadership positions. He was a sharp critic of President Bill Clinton's healthcare proposals and sought the GOP presidential nomination to run against him in 1996. But two years later he would go on to vote "not proven" during Clinton's impeachment hearings, believing the president had not received due process.
As Judiciary Committee chair in 2006, he called then-Attorney General Alberto Gonzalez to testify on the Bush administration's warrantless wiretapping of U.S. citizens, a practice he openly criticized.
During the scandal the same year around the leaking of CIA operative Valerie Plame's identity, Specter said President Bush, "owes a specific explanation to the American people," over the circumstances, adding that even if "the president may be entirely in the clear, and it may turn out that he had the authority to make the disclosures which were made, it was not the right way to go about it because we ought not to have leaks in government."
Specter's Party Switch From Republican to Democrat
Besides his time spent on Capitol Hill, Specter may be best known for his 2009 party switch, which played a key role in helping President Obama get his flagship legislation though Congress.
Specter called his decision to switch from Republican to Democrat "painful," and said he made the decision based on public and private polling in Pennsylvania that showed "the prospects for winning a Republican primary [in Pennsylvania] are bleak.
"As the Republican party has moved farther and farther to the right, I have found myself increasingly at odds with the Republican philosophy and more in line with the philosophy of the Democratic Party," Specter said at the time..
Senate Republican leaders admitted they were unhappy losing a member, but argued that it had nothing to do with the national Republican Party rejecting moderates, but only with local Pennsylvania politics and Specter's desire for "political self-preservation."
In 2010, Specter lost the Democratic primary to then-U.S. Rep. Joe Sestak, who in turn lost the race to Republican Pat Toomey.
Specter supported the Obama administration's controversial American Recovery and Reinvestment Act -- the stimulus -- and Wall Street reform as efforts to get the economy back on track after the collapse of 2008.
But perhaps most stinging to the Republican party, Specter's vote was the magic number 60th vote, to pass Obama's health care reform legislation in the Senate in December 2009.
In March of this year Specter spoke out about what he saw as the gridlock that has all-but paralyzed Congress this year.
"The cannibals have taken over and it has produced a gridlocked Senate and a dysfunctional government," Specter said in an interview with CBS News. "Like cannibals eating their own, that's what's happening in Washington. ... You had a senator like Bob Bennett, with a 93 percent conservative rating, he cast one vote to support the bailout of the auto industry and he got dumped by the Republican Party."
Senate Majority Leader Harry Reid, D-Nev., released the following statement today on Specter's passing:
"I was deeply saddened today to learn of the passing of Senator Arlen Specter. I served with Senator Specter in Congress for twenty-eight years. Senator Specter was a man of moderation; he was always passionate, but always easy to work with. I followed him through his previous illnesses, during the course of which he displayed great physical strength and great strength of character. Throughout his life, Senator Specter fought and won many battles, but this was one he could not win," Reid said in the statement. "America is better today because of Arlen Specter. He will be dearly missed."
After he left politics, Specter resumed his former career as an attorney, and served at his former alma mater, the University of Pennsylvania, as an adjunct law professor.
He was even seen touring the Philadelphia comedy club circuit, jokingly lamenting over his days on the Hill, Bill Clinton, and former Pennsylvania Gov. Ed Rendell.
ABC News' Zach Wolf and The Associated Press contributed to this report.