After an awkward delay, Washington officials joined a global chorus of outrage after dozens of civilians were killed by a suspected chemical agent in a strike on a rebel-held town.
The White House said it was confident that Bashar al-Assad's regime was to blame, and US officials said his allies Russia and Iran must bring the dictator to heel.
"While we continue to monitor the terrible situation, it is clear that this is how Bashar al-Assad operates: with brutal, unabashed barbarism," Secretary of State Rex Tillerson said.
In a separate statement, President Donald Trump criticized his predecessor Barack Obama's "weakness and irresolution" in failing to punish previous Syrian chemical attacks in 2013.
But no senior figure appeared on camera to denounce the attack. Tillerson ignored questions from reporters and Trump went ahead with an address to building workers without mentioning it.
Next week, Tillerson will visit Moscow for talks with the government of President Vladimir Putin, Assad's main military and diplomatic backer in Syria's six-year-old civil war.
"We call upon Russia and Iran, yet again, to exercise their influence over the Syrian regime and to guarantee that this sort of horrific attack never happens again," he said.
"As the self-proclaimed guarantors to the ceasefire negotiated in Astana, Russia and Iran also bear great moral responsibility for these deaths," he warned.
The Syrian army and Russia have categorically denied involvement in the strike on Khan Sheikhun.
The latest attack came as Trump's administration was already struggling to explain its policy towards Syria, beyond rejecting Obama's previous strategy.
Assad not the priority
Building on Trump's bellicose campaign rhetoric, the core of the new approach was to be a single-minded re-focusing of US efforts towards the defeat of the Islamic State group.
This ambitious jihadist force exploited the disorder thrown up by Syria's civil war, which allowed it to seize Raqa in eastern Syria and a pocket of land leading to the Iraqi city of Mosul.
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But the IS group is already on the back foot after a campaign by US-backed local forces that began under Obama, and Assad's war against his domestic opposition is a far deadlier conflict.
Under Obama, Washington hoped to defeat the Islamic State group on the battlefield while working with Russia and US Arab allies to pressure Assad and his civil war opponents to negotiate peace.
Back in 2013, Obama warned Assad his use of banned chemical weapons against his own people crossed a "red line", but he famously decided not to order US intervention.
Instead, then secretary of state John Kerry negotiated a deal with Russia to oversee the dismantling of Assad's declared chemical stockpiles, although it is now obvious some remained.
Under Trump, new secretary Tillerson's job is to get Russia on board with the battle against "radical Islamic terrorism" and, until this week, Assad's fate was far from a priority.
Last week, Tillerson said the "status of president Assad will be decided by the Syrian people" -- tacitly aligning Washington with Russia's plan to allow him to seek re-election.
Nikki Haley -- the US ambassador to the United Nations and increasingly the voice of US foreign policy compared to the taciturn Tillerson -- underlined this choice.
Pick your battles
"You pick and choose your battles," she told reporters.
"And when we're looking at this, it's about changing up priorities and our priority is no longer to sit and focus on getting Assad out," she explained.
Haley later walked this back, declaring Assad a "war criminal" and insisting that the Syrian people themselves reject him.
But even after Tuesday's chemical attack, Trump's spokesman Sean Spicer admitted that Assad's rule is a "political reality" and that there is no "fundamental option of regime change."
This will be welcome news for Putin as he prepares to receive Tillerson on Wednesday next week, but it outraged Washington hawks who see Trump as going soft on a bloody dictator.
Republican Senator John McCain derided the idea the Syrian people would be able to decide on the future of Assad while under bombardment by him as "an absurd fiction."
And, in a nod to Tillerson and Haley, he said: "The recent statements by US officials suggesting otherwise only serve to legitimize the actions of this war criminal in Damascus."