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Sons of drugs kingpin "El Chapo" are among members of Mexico's Sinaloa cartel charged in the United States with running a huge operation that supplies fentanyl to the US.
The operation was allegedly fuelled by Chinese chemical companies.
Fentanyl is responsible for the deaths of tens of thousands of mainly young Americans each year.
Joaquín "El Chapo" Guzmán, the former Sinaloa cartel leader, is serving a life sentence in the US.
His three sons charged - Ovidio Guzmán López, Jesús Alfredo Guzmán Salazar and Iván Archivaldo Guzmán Sálazar - are known as the Chapitos, or little Chapos, and are believed to be the more violent faction of the cartel.
"They know that they're poisoning and killing Americans. They just don't care because they make billions of dollars doing it," Anne Milgram, chief of the US Drug Enforcement Administration, said of Guzman's sons.
"Their greed is shocking and without bounds."
Federal prosecutors announced three separate indictments charging 28 defendants based in Mexico, China and Guatemala, eight of whom are in custody.
Attorney General Merrick Garland called it "the largest, most violent, most prolific fentanyl trafficking operation in the world".
Fentanyl is a synthetic opioid that is up to 50 times stronger than heroin and 100 times stronger than morphine, according to the United States' Centers for Disease Control and Prevention (CDC).
Ovidio Guzman Lopez, one of El Chapo's sons nicknamed "The Mouse" who was arrested in Mexico earlier this year, is the only brother in custody and awaiting extradition.
At least 29 people were killed during the bloody operation to arrest him in January. Furious gang members set up road blocks, set fire to dozens of vehicles and attacked planes at a local airport.
He was indicted in a Manhattan federal court on six counts, including conspiracy to import and distribute fentanyl. He faces life in jail.
Prosecutors also charged four owners of Chinese firms accused of providing chemicals to the cartel.
The US Treasury Department hit two China-based chemical companies with sanctions.
Mr Garland said that the Chinese government "must stop the unchecked flow of fentanyl precursor chemicals that are coming out of China".
A record number of nearly 107,000 Americans died of drug overdoses in the US in 2021, according to the CDC.