George Bush arrived in the Mexican resort town on Wednesday night and will have a series of one-on-one meetings with Vicente Fox, the Mexican president, and Stephen Harper, the newly elected conservative prime minister of Canada.
Joint sessions with the three leaders will follow on Friday.
The official focus of the summit between the US and its two largest trading partners is a the Security and Prosperity Partnership pact designed to make borders more secure without hampering business and traffic.
But Fox and Harper are in Cancun with more on their minds. Both have powerful constituencies at home pressing for progress on problems related to the enormous flow of goods and people between their countries and the US.
Mexico's top priority with its northern neighbour is a migration accord that would address the status of the estimated six million illegal immigrants from Mexico living in the US.
For Canada, the main issue with the US is a trade dispute over softwood lumber.
Bush extended an olive branch in both directions before leaving on his trip. He told foreign reporters not to underestimate his ability to push through Congress a guest-worker programme that would address some of Mexico's concerns, and said he wants to solve the issue of Canadian lumber tariffs.
He departed Washington for his meetings with Fox as an emotional election-year dust-up over immigration continued to rage in the US capital.
The issue has seen hundreds of thousands protestors take to the streets across the US and split the president's Republican Party as mid-term congressional elections approach.
Security is tight at the popular
The Senate was debating a measure that would strengthen border security, but also would legalise some undocumented workers, establish temporary guest-worker programmes and permit illegal immigrants currently in the country to apply for citizenship without first returning home.
The business community and a minority of Republicans in Congress have supported such moves, and the approach dovetails more with what Bush has advocated than competing House legislation that focuses on an illegal immigration crackdown.
Fox wants some form of legal status for all undocumented Mexicans but sees a guest worker programme as a good step.
If one is approved before July elections to succeed him, analysts believe it could boost the chances of the candidate from his party.
As for Harper, the newly elected Conservative leader has made it a priority to restore Ottawa's relationship with Washington, which has been strained over Iraq, missile defence and a series of trade issues.