To Iran, the United States was the "Great Satan," while Washington slammed Tehran as a "rogue state" that was part of an "axis of evil."
But as chaos engulfs the Middle East, the two are cautiously eyeing ways to work together.
An ideological chasm separates the Shiite Islamic republic from its long-time enemy in the West, yet overlapping concerns from Afghanistan to Syria and even Iraq are sowing the seeds of a hesitant rapprochement.
Restoring full diplomatic ties, severed some 35 years ago amid the 1979 storming of the US Embassy in Tehran and the painful 444-day hostage-taking, remains far off on a distant horizon.
But the willingness of the Obama administration to engage in secret negotiations in Oman last year and the new leadership of Iranian President Hassan Rouhani have already borne fruit, facilitating an interim deal in November on reining in Iran's nuclear program.
"There is a high degree of pragmatism in the way the two countries are approaching each other, and it partly arises from a lack of other options," said John Bradshaw, executive director of the National Security Network.
"The US has strong allies, like Israel, but is looking to find other pragmatic ways to help us achieve our goals," he told AFP.
Afghanistan is one place where the concerns of both countries converge, with neither wanting to see the Taliban regain power.
And there is historic precedent, highlighted Alireza Nader, senior international policy analyst with the RAND Corporation, pointing to their cooperation in setting up a post-Taliban government in 2001 and 2002.
Both countries are also "concerned about narcotics emanating from Afghanistan. That is a huge problem for Iran, " he said.
"If the nuclear issue is resolved, I see that possibly as the best case for cooperation."
Syria is another theater where, despite being on opposite ends of the conflict, both want to see an end to the fighting and thwart any rise by extremist Sunni Al-Qaeda militants.
Top US diplomat John Kerry has hinted that despite Iran's fully-fledged support for Syrian President Bashar al-Assad, which has included plying him with arms, cash and military advisers, Tehran might be able to play a role on the sidelines of Syria peace talks later this month.
Using its sway over Damascus to halt the bombardments of civilians and open up humanitarian corridors would be a way for Tehran to show that it aims to be a constructive player, US officials have said.
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But while Washington is motivated by ending the fighting and ousting long-time foe Assad, Iran wants to retain its hold over a country that has long been a conduit to funnel weapons to Lebanon-based Hezbollah militants, seen as a front against America's staunch ally, Israel.
Mutual opposition to the rise of Al-Qaeda extremists could also lead to a paradoxical cooperation in Iraq.
Iran's deputy chief of staff General Mohammad Hejazi said last weekend that his country was prepared to provide military equipment and advice to Iraq to help it flush Al-Qaeda out of Anbar province.
"As a country that is trying to develop economically and becoming more of a pragmatic player, regionally and globally, they (Iranians) have a strong interest in seeing that Sunni extremism, Al-Qaeda and other groups, are not a destabilizing factor for them and the region," explained Bradshaw.
It's clear though that driving both the US and Iranian agendas is a singular desire to shore up their own influence in a region convulsed by recent political upheavals.
"Both countries are still in competition for the Middle East," stressed Nader, and while they might be able to cooperate, that "does not mean that the US and Iran become allies, rather it is just a potential process of engaging each other to resolve some regional issues."
The warming ties have been angrily received in Israel, and by other US allies such as Saudi Arabia, while Republicans are also wary of approaches to a country they consider hostile and untrustworthy.
Indeed, Iran is still viewed by the United States as the world's number one sponsor of state terrorism.
Getting Iran to help fight Al-Qaeda is like "the arsonist offering to put out the fire," wrote Raymond Tanter, who served on the National Security Council staff in Ronald Reagan's administration, in Foreign Policy magazine.
"The idea that Tehran and Washington face common enemies and hence should be friends overlooks Iran's facilitation of those adversaries."
And White House Iran adviser Puneet Talwar, who took part in the secret Oman talks, told lawmakers last month that "it's tricky business to try to see into the internal workings of Iran at any given moment."
He added, however, that he did see Rouhani's election as a "cry for change" from the Iranian people that could put pressure on the government.
Analysts in Washington are already trying to envisage a future in which Iran and the US restore diplomatic ties.
"It would be a long process toward full normalization," said Bradshaw.
"But we've done it with other countries, and it's something that's possible even after long years of hostility. But it's not something that happens very quickly."