John Kerry has reaffirmed the "special relationship" between the US and Britain as he made London his first overseas stop after being appointed Secretary of State.
Mr Kerry, who has replaced Hillary Clinton, held breakfast talks with David Cameron before a meeting with Foreign Secretary William Hague.
Tensions over Iran's nuclear ambitions, the Syrian civil war, the Middle East peace process and the prospect of a US-EU free trade zone were all discussed.
Britain's row with Argentina over the future of the Falklands was also covered, although Mr Kerry refused to comment publicly on next months' referendum.
The Prime Minister is the first world leader to host talks with Mr Kerry since his appointment as Barack Obama's foreign affairs supremo.
London is his first stop on a tour which will also take in Germany, France, Italy, Turkey, Egypt, Saudi Arabia, the United Arab Emirates and Qatar.
At a joint press conference with Mr Hague, he said it was "no accident" that he had chosen America's "remarkable partner" as the starting point.
"When you think of everything that binds the US and Great Britain - our common values, our long shared history, our ties of family and friendship, there is a reason why we call this the special relationship, or as President Obama and Prime Minister Cameron wrote, "a partnership of the heart"," he said.
"In the 20th century, our countries fought for freedom side by side and fought for survival together in war, we thrived together in peace and we stood together time and time again in order to meet the world's great challenges.
"In the 21st century, we may face a new and more complex set of challenges, but I absolutely know that we face them together just as we did in the last century. And together, it is absolutely clear that our partnership remains stronger than ever."
Mr Kerry described the proposals for a trans-Atlantic trade agreement as "historic". "It's no secret that we both face economic challenges - we all do in this new global marketplace," he said.
"The fact is that Europe, free-standing, alone, is the largest economy in the world. When you join that together with the USA, we have a powerful ability to be able to affect the rules of the road and to be able to raise standards and, most importantly, create jobs for all of our people."
On the Falklands, he said the US position had not changed and that it recognised the "de facto UK administration".
America would take no position on the issue of sovereignty, he added, and stressed that the UK and Argentina should cooperate on "practical matters".
On a personal note, the American recalled how he visited London as a young child and got lost at the zoo, adding: "I want to thank somebody for finding me."
Mr Hague said the relationship between the UK and US was an "indispensable alliance" and that the talks had been "detailed and very thorough".
This week's tour sees Mr Kerry, the son of a diplomat, return to familiar ground. He spent part of his childhood in Berlin, has family in France and is a keen supporter of strong transatlantic ties.
Syria will crop up throughout the trip, and a senior US administration official travelling with him has urged the opposition not to boycott international talks due to be held in Rome on Thursday.
"We are stressing ... that they (the opposition) have an opportunity in Rome, to see the countries that have been their greatest supporters and to present to all of us how they see the situation on the ground in security, humanitarian, political and economic terms," he said.
"This meeting is also an opportunity for them to meet our new Secretary of State and to speak directly to him."
Mr Kerry arrives in Paris on Wednesday for talks with French President Francois Hollande and Foreign Minister Laurent Fabius.
There, Mali - where the Americans are providing logistical support to French forces - Iran, Syria and North Korea will all be on the agenda.