Since Netanyahu and Obama came to power in 2009 they have had a testy relationship, clashing over Israeli settlement building and the moribund Middle East peace process.
But on Tuesday, Netanyahu will appear in Obama's backyard, at Republicans' invitation, and ask Congress to oppose a policy the White House views as pivotal to US national security and to the president's legacy.
Netanyahu's goal is simple: try to kill a US nuclear deal with Iran, even if it destroys relations with Obama in the process.
To Netanyahu's eyes, the deal -- now in the final stages of negotiation -- would give Iran's Ayatollahs tacit permission to seek a nuclear weapon when it expires a decade or so from now.
While a nuclear-armed Iran could threaten Israel's existence and spark proliferation across the Middle East, sabotaging the deal would offend a US president who will be an ex-president in two short years.
"I respect the White House and the US president but on a serious subject, it's my duty to do everything for Israel's security," Netanyahu said before leaving for Washington.
Diplomats believe Obama could agree and implement most of the deal without Congress's help, but lawmakers keen to show their pro-Israel credentials ahead of the 2016 US election could make life difficult.
Their refusal to lift some sanctions or even introduce more could incite Iran to walk away.
'SEE HIM GONE'
Faced with Netanyahu's perceived foray into domestic US politics, an infuriated White House has pushed back hard, to the point of undermining the Israeli leader ahead of his March 17 re-election bid.
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National Security Advisor Susan Rice pointedly described Netanyahu's speech and the manner it came about as injecting a measure of partisanship that was "destructive of the fabric of the relationship" between the two countries.
Obama has refused to meet the Israeli prime minister when he visits Washington and moderate Democrats have vowed not to attend the speech.
The US Vice President and Secretary of State will be out of the country when Netanyahu visits.
"They are trying to send an unmistakable signal in advance of the elections that he is not their candidate," said Aaron David Miller, a former advisor to Republican and Democrat secretaries of state.
"They can't say that, they would deny it, but let's be clear: they would like to see him gone."
Whether that paints Netanyahu as isolated or resolute in the eyes of Israeli voters remains to be seen, and he remains in a strong position in the polls.
With re-election a definite possibility, pro-Israeli groups in Washington want to prevent a Obama-Netanyahu row from metastasizing into a strategic divergence between the US and Israel.
"At a 40,000-foot level, you find strategic alignment around goals, where you find difference is around the two ruling parties," said Jeremy Ben-Ami, president and founder of J-Street, a left-leaning lobby group.
But if Netanyahu wins, Ben-Ami predicted he is likely to consider unilateral military action against Iran, even if there is a deal, a potential flashpoint for US-Israeli ties.
"The Prime Minister is playing with fire in stoking this dispute so much," Ben-Ami told AFP.
"Over the long term it may do harm to the bipartisan consensus around the basic commitment that the US has and that's a real risk that Israel's leaders shouldn't be taking."
A string of Democratic lawmakers are voting with their feet, announcing they will not attend Netanyahu's speech.
"Too much of this is about the rhetoric and politics," said Democratic Senator Tim Kaine.