Syrian leader Bashar al-Assad should have no role in a future Syria, US Secretary of State Rex Tillerson says.
Signalling a shift in US policy, he called for "a political process that would lead to Assad leaving".
His remarks follow a suspected chemical attack in Syria, which US President Donald Trump called a "disgrace to humanity".
The US is said to be mulling possible military action in Syria, although it is unclear what that might entail.
Measures reported to be under discussion between the Pentagon and the White House are the grounding of Syrian warplanes and the setting up of safe zones for civilians.
Mr Tillerson's comments signal an apparent U-turn for the US - only last week the US ambassador to the UN, Nikki Haley, said Washington was no longer prioritising the removal of President Assad.
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Mr Tillerson had also said Mr Assad's long-term future would "be decided by the Syrian people".
But speaking in Florida on Thursday, Mr Tillerson said: "Assad's role in the future is uncertain and with the acts that he has taken, it would seem that there would be no role for him to govern the Syrian people.
"We are considering an appropriate response (to the) violations of all previous UN resolutions, violations of international norms."
He said "steps were under way" to organise an international coalition to remove Mr Assad.
Addressing reporters on his way to Florida to meet Chinese President Xi Jinping, Mr Trump said: "I think what Assad did is terrible. I think what happened in Syria is a disgrace to humanity and he's there, and I guess he's running things, so something should happen."
UN Secretary-General Antonio Guterres, asked if he was concerned about possible US military action in Syria, said his priority was to ensure accountability for the deadly gas attack.
He said he could not comment on "things that have not yet happened."
Dozens of people, including at least 27 children, are reported to have died following an attack on the town of Khan Sheikhoun in Idlib province early on Tuesday.
Evidence has mounted that the victims were killed with a nerve agent such as Sarin.
Syria has denied dropping chemical weapons from the air and its key ally, Russia, had argued that the mass poisoning was caused by an air strike on a rebel weapons dump where chemical weapons were being stored.
But the claims have been viewed with scepticism from the US and its allies.
Syria says it would only accept a UN investigation into the incident if a list of conditions are met.
Source: BBC