Crowds in Tehran have been shouting the same chant for more than a quarter century: “Death to America!”

The threat takes on new meaning — and new menace — with the real prospect that one of the oldest civilizations on Earth may be developing nuclear weapons.

Complicating matters is the issue of who would control these weapons. Iran is a theocracy that makes different foreign policy calculations than democracies or dictatorships.

“To have a despotic theocracy in the possession of a nuclear weapon … creates a much greater danger than having a democratically elected government in control of a nuclear weapon,” said Sen. Joe Biden (search) of Delaware, the top Democrat on the Senate Foreign Relations Committee.

“They are much, much more likely to use it — or threaten to use it — or attempt to use it, for blackmail,” he told FOX News.

This much is certain: an Iranian bomb would be a crushing setback for President Bush, whose doctrine of "pre-emption" is based on the policy of keeping the world's most dangerous weapons out of the hands of the world's most dangerous people.

“This administration's entire foreign policy, in the name of which we have fought two wars, in Afghanistan and in Iraq, would look hollow,” said Walter Russell Mead (search), a senior fellow for U.S. foreign policy at the Council on Foreign Relations.

“I think it's a realistic threat that Iran could give nuclear weapons to terrorists,” Mead said.

Bush highlighted the treaty in the 2002 State of the Union Address. “The United States of America will not permit the world's most dangerous regimes to threaten us with the world's most destructive weapons,” he said.

The world learned how terror could cripple a superpower when Iranian students held 52 Americans hostage for 444 days from 1979-1981. But the attacks against American interests didn’t stop there.

Soon after Iran began funding Hezbollah (search), the radial group based in Lebanon carried out a 1993 truck bombing that killed 241 U.S. Marines. And Iran also supported another terror cell that in 1996 truck-bombed the Khobar towers in Saudi Arabia, a complex which houses U.S. Air Force personnel. Nineteen Americans were killed and 372 were wounded.

“Iran is the mother of modern terrorism,” said Michael Ledeen, a scholar at the American Enterprise Institute. “Every time you turn around to look at terrorism in the Middle East, you find Iran.”

Perhaps more worrisome for Americans are the links between Iran and Al Qaeda (search) found by the U.S. commission that investigated the Sept. 11, 2001, attacks.

In the early 1990s, the commission said, Iranian operatives struck a deal with Al Qaeda to coordinate terror attacks against Israel and the United States. The panel said that in the 1990s, Al Qaeda was trained by the Iranian-sponsored terror group Hezbollah. And after Al Qaeda bombed the USS Cole in October 2000, Iran tried to strengthen relations with Al Qaeda, the panel found.

While the commission stopped short of saying Iran had an active rule in the Sept. 11 attacks, it expressed suspicion that as many as 10 of the hijackers traveled through Iran on their way to the United States. And the CIA has reported that hundreds of Al Qaeda members are being harbored by the ayatollahs in Iran.

“To have these people armed with atomic bombs is truly nightmarish,” Ledeen said.

The nightmare does not end with Iran passing an atomic bomb to terrorists. Iran already has missiles capable of carrying nuclear warheads that could strike Israel and even Europe.

Biden said the tension surrounding Iran nears Cold War proportions.

“It ratchets up everything,” Biden said. “It makes the neighborhood a hell of a lot more dangerous.”

What can the United States do about it? Diplomacy is the first hope but American officials have little trust for their Iranian counterparts after Iran was caught secretly developing an advanced nuclear program violating its international agreements and then lying about it.

“They've never told the truth on anything we've ever confronted them with,” said Sen. Rick Santorum (search), R-Penn., who has written legislation to turn up pressure on Iran. “They will lie in order to get what they believe is necessary to protect this regime.

“I don't think it's a good idea to negotiate with people that you can't trust.”

Santorum said he agrees with Bush that the United States can't allow Iran to get nuclear weapons. But he's against offering the clerics ruling Iran economic incentives and he won't commit to what might seem like the other logical step.

“Right now, I don’t think that we have good enough information that we can act, and nor do I believe that we, at this point, have the intelligence to know where that, where that strike would even be,” Santorum said.

Seventy percent of Iran's population is under age under 30 — too young to remember the Ayatollah Khomeini or the American hostage crisis. And a democratic reform movement has brought new hope for social liberalization, although the clerics have put that down for now.

So what Santorum is calling for is regime change — though he's reluctant to use those words.

To help democratic groups succeed, Santorum has introduced a bill to support the pro-democracy groups with funding and to penalize firms and countries that do business with Iran.

One supporter of Santorum is Ledeen, the American Enterprise Institute scholar who has long pushed for regime change in Iran.

“Believe me, if the regime in Iran comes down, it will change the whole world, it'll be a really dramatic event,” Ledeen said.

“The nuclear status of Iran is neither here nor there with regard to the war on terror. The only thing that matters with regard to the war on terror is whether that regime is there, or whether it's gone. That's the whole issue.

Does Santorum think it's possible that the pro-democratic forces in Iran are close to toppling the mullahs?

“Do I believe they’re close now? No, I don’t believe they’re close. What I do believe is that … we need to be there to be supportive of a fair and democratic elections process in Iran, which obviously this regime will never accept.”

Bush himself advocates regime change.

“I believe that the Iranian people ought to be allowed to freely discuss opinions, read a free press, have free votes, be able to choose amongst political parties. I believe Iran should adopt democracy. That's what I believe,” Bush said March 16.

Biden said such a view is “not unrealistic.”

“Can you base your policy on that certainty of that outcome? No. Is it a gambit that is worth trying while at the same time, you are preparing for the worst-case scenario? Yes.”

For Biden, the worst-case scenario is the United States having to strike again in that part of the world.

“I would not take military force, off the table. Period,” Biden said. “But the truth of the matter is … this is calculus, not arithmetic. Arithmetically, it doesn't look good ... The calculus — there are a lot of pieces on the board moving.”

FOX News' Chris Wallace, Brian Gaffney and Grace Cutler contributed to this report.