The new era began with little fanfare when an agreement between the two nations to resume normal ties on July 20 came into force early Monday morning and the diplomatic missions of each country were upgraded from interests sections to embassies.
In yet another historic gesture, US Secretary of State John Kerry will also formally receive his Cuban counterpart Bruno Rodriguez for talks, before holding a joint press conference around 1:45 pm.
Rodriguez will earlier preside over a ceremony to mark the upgrading of the Cuban interests section to a full embassy.
The remarkable turnaround in relations between the communist authorities in Cuba and the US administration after five decades of hostility has happened at break-neck speed.
In what will mark a foreign policy legacy for US President Barack Obama, he and his Cuban counterpart Raul Castro agreed on December 17 to end their estrangement and put their countries on track towards a full normalization of ties.
After a series of negotiations in Havana and Washington, the restoration of diplomatic ties has come about just seven months later.
But both nations have cautioned that this is only a beginning, warning overcoming decades of enmity is not easy.
There are "issues that we don't see eye-to-eye on," State Department spokesman John Kirby admitted Friday.
The United States "wants to move beyond a Cold War-era approach to one of constructive engagement as a way to support and empower the Cuban people," analyst Ted Piccone from the Brookings Institution told AFP.
"Cuba needs the United States as an economic engine for its troubled economy and hopes to attract new foreign investment and human capital to update its socialist model, but without undergoing political reform."
"Building confidence and trust will be critical to the ability to move forward," he added.
One of the biggest areas of contention remains human rights, with Washington pressing for an improvement in freedoms of expression, religion and the press in the Caribbean island nation.
Some Republicans have been sharply critical of the US haste to cozy back up to Cuba.
Senator and 2016 presidential hopeful Marco Rubio, the son of Cuban immigrants, told CNN: "I would end the diplomatic relations with anti-American communist tyranny until such time as they actually held a democratic opening in Cuba."
"This recognition somehow sends a message to dissidents and others around the world that the United States accepts the Cuban form of government today as a legitimate form of government," Rubio argued.
Another tough issue is compensation for American property seized after the 1959 Cuban revolution led by Fidel Castro. Some 5,911 lawsuits have been opened in the United States with an estimated value of $7 billion to $8 billion.
On Havana's side, Raul Castro has urged Obama to use his executive powers to "dismantle" the economic embargo in place since 1962, calling it the main stumbling block towards normalization between the two nations.
Washington also wants to ensure the return of several American fugitives wanted in the United States.
Top of the list is former member of the violent Black Panther revolutionary group, Joanne Chesimard, wanted for the killing of a New Jersey policeman in 1973 and who has been hiding in Cuba since 1984.
The US interests section in Havana will also be upgraded to a full embassy, but with little fanfare as diplomats there await the arrival of Kerry, who is due to officially hoist the American Stars and Stripes over the building later this summer.
Tough negotiations eased one stumbling block, top US diplomat for Latin America Roberta Jacobson said, after insisting that American diplomats be allowed to operate freely across Cuba.
"The security presence outside the intersection has already been reduced... such that we hope people will not feel nearly the same kind of presence or threat," she told lawmakers.
And while American diplomats would still have to provide notification of their travel, they will no longer have to seek permission.