The Prime Minister announced the start of formal negotiations on a trade deal worth hundreds of billions of pounds, aimed at boosting exports and driving growth.
Cameron said a successful agreement would have a greater impact than all other world trade deals put together.
The talks were announced ahead of the G8 summit in Northern Ireland and US President Barack Obama said the first round of negotiations would take place in Washington in July. They aim to conclude by the end of 2014.
Mr Obama said he was confident of reaching an agreement.
“There are going to be sensitivities on both sides… but if we can look beyond the narrow concerns to stay focused on the big picture… I’m hopeful we can achieve [a deal].”
Cameron said the deal could be worth £100bn to the EU economy, £80bn to the US and £85bn to the rest of the world, adding that the pact could create two million jobs, and lead to more choice and lower prices in shops.
“This is a once-in-a-generation prize and we are determined to seize it,” said Cameron.
Herman Van Rompuy, the president of the European Council, said: “Together Europe and the United States are the backbone of the world economy. Opening up that space further for opportunities for business and consumers is simply common sense.”
The trade talks had been under threat from a potential veto from France, but on Friday EU ministers agreed to French demands to exclude the film and television industry from the talks.
Some had argued that omitting the media business from the trade talks even before they had begun could prompt the US to seek exemptions for other sectors.