The US has charged Venezuela's President, Nicolás Maduro, and other senior officials in the country with "narco-terrorism".
It accused them of flooding the US with cocaine and using drugs as a weapon to undermine the health of Americans.
The charges were announced by Attorney General William Barr. A $15m (£12.5m) reward is being offered for information leading to Mr Maduro's arrest.
The US move will further escalate tensions between the two nations.
Washington has long accused the Venezuelan president of leading a corrupt and brutal regime, a charge he has repeatedly rejected.
It backs the opposition leader Juan Guaidó, who declared himself interim president last year.
The new charges represent an escalation in the longstanding US pressure campaign on Mr Maduro, which also includes sweeping sanctions on Venezuela's oil industry.
As well as Mr Maduro, the US charged more than a dozen top Venezuelan officials. These included the country's defence minister and the supreme court's chief justice.
"The Venezuelan people deserve a transparent, responsible, representative government that serves the needs of the people - and that does not.... engage in illicit narcotics trafficking," the US state department said.
The charges against Mr Maduro and 14 members of his inner circle include narco-terrorism, drug trafficking, money laundering and corruption.
At a news conference announcing the indictment on Thursday, Mr Barr accused Mr Maduro of conspiring with a faction of the Colombian Farc rebel group "to flood the United States with cocaine" and "devastate American communities".
"While the Venezuelan people suffer, this cabal... lines their pockets," he added.
Mr Barr said the Colombian rebels had "obtained the support of the Maduro regime, who is allowing them to use Venezuela as a safe haven from which they can continue to conduct their cocaine trafficking".
"Maduro very deliberately deployed cocaine as a weapon... to undermine the health and wellbeing of our nation," US Attorney Geoffrey Berman said.
He accused Mr Maduro and his top aides of running a "narco-terrorism partnership with the Farc for the past 20 years".