After winning his fifth Senate race in 2008, Kerry became chairman of the Senate Foreign Relations Committee the next January. He has had a powerful voice outside the Obama administration in his current role.
But sources close to the Massachusetts Democrat note that the increasing partisanship on Capitol Hill has disillusioned Kerry and he is ready to leave the Senate.
Kerry will come to the post with a full plate of foreign policy crises, including the civil war in Syria, the nuclear antics of North Korea and a looming showdown with Iran over its nuclear program.
Anybody who follows Clinton would have some pretty big shoes to fill. Clinton was not just the most popular member of the president's Cabinet for the past four years, she had celebrity status and respect almost everywhere she went around the world.
Burns said it's not a job for "the faint of heart."
"It is for someone with a deep, deep reservoir of knowledge, he said, and "Kerry has that kind of knowledge."
Many have noted the esteem Kerry has gained on the world stage through his role as chairman of the Senate Foreign Relations Committee for almost 30 years, the last four as chairman.
"I think he has been an unusually effective chairman," Burns said. "He has not only been the chair of the committee in trying to unite Democrats and Republicans on the top foreign policy issues facing our country, but he has been a diplomatic troubleshooter for the administration. So he has really played two roles over the president's first term."
While Obama is not close to a lot of world leaders, Kerry has deep relationships with many heads of state that he can draw on as the nation's top diplomat.
He is no stranger to diplomacy and has often traveled overseas on behalf of the Obama administration as a diplomatic troubleshooter and to mend frayed relationships. Kerry persuaded Afghan President Hamid Karzai to agree to an election runoff in 2009, and he traveled to Pakistan after a series of incidents, including the raid that killed bin Laden.
"The president did not give him tertiary assignments," Burns said. "The president asked him to take on the toughest issues -- the war and peace issues in which we are currently engulfed in trying to determine how do we get out of Afghanistan. How do we stabilize our very difficult and disputatious relationship with Pakistan? How do we stabilize well the nuclear balance between India and Pakistan? He was very much involved in Sudan as well, and so I think this is very good experience, obviously, that qualifies him to be secretary of state. It also means that there is an element of trust already there between President Obama and Senator Kerry."
Like Obama, Kerry sees the benefit of reaching out to adversaries, like Iran and Syria, and giving them a chance to negotiate. At one point, Kerry even spearheaded outreach efforts to Syrian President Bashar al-Assad before the administration turned on al-Assad because of his crackdown on protesters. But he also has called for arming the opposition and for NATO airstrikes, which Obama's administration has resisted.
The Middle East would be sure to take up a good part of the secretary's time. In addition to helping bring about a political transition in Syria, the United States also must manage the political chaos in Egypt and the rest of North Africa while trying to negotiate a nuclear deal with Iran and revive the Middle East peace process.
Kerry is well-traveled to the Middle East, has a good feel for the region and knows many of the players. Insiders say a Secretary of State Kerry would want to play a big role in shaping Mideast policy and try to help solve some intractable issues, including delving heavily into the peace process.
Kerry also has displayed a particular interest in climate change and energy, and sources say he is likely to give special emphasis to those issues. His wife, Teresa Heinz Kerry, has used some of her fortune to support environmental groups.
Unlike Rice, Kerry is not seen as an Obama insider, but he has been a presence at key moments in Obama's rise.
He served with then-Sen. Obama on the Foreign Relations Committee and, as a presidential nominee in 2004, gave the young senator a platform on the national stage when he asked him to speak at the Democratic National Convention. In this election, Kerry also helped prep Obama for his debates with Mitt Romney and offered a strong argument of the administration's foreign policy during his address at the convention in September.
Obama is considered a president who likes to drive foreign policy himself, and the White House plays a major role in both its conception and execution.
There's a question of whether Obama will empower Kerry to fashion areas of foreign policy on his behalf. Miller, the Middle East expert at the Wilson Center, cites legendary former secretaries such as Henry Kissinger, James Baker and George Schultz as diplomats who were empowered to create the policies that their presidents then implemented.
"That is going to be the difference, I think, between John Kerry being a good secretary of state and ... truly be a consequential, if not great, secretary of state," Miller said.