The New York trial began on Monday under razor tight security for Joaquin "El Chapo," accused of running the world's biggest drug cartel and spending a quarter of a century smuggling more than 155 tons of cocaine into the United States.
Guzman, one of the most notorious criminals in the world, sat in court sporting a navy suit, white shirt with a wide disco-style collar and various buttons undone, flashing a smile for the start of jury selection.
The marathon Brooklyn federal trial, which will cost millions of dollars and is expected to last more than four months, will see Guzman face the US justice system after twice escaping prison in Mexico, once hidden in a laundry cart and then slipping down a tunnel that reached his prison shower.
US prosecutors have spent years piecing together a sweeping case against Guzman, which they hope will end with the 61-year-old spending the rest of his life in a maximum-security US prison.
Opening arguments are scheduled to start on November 13, after a week set aside for jury selection, held behind closed doors with only a select "pool" of reporters admitted under the tightest security reserved for the most dangerous defendants.
Of about 100 potential jurors, 19 were interviewed by Judge Brian Cogan early Monday, with another 20 set for the afternoon. Five were dismissed by lunchtime with no one yet impaneled.
The 12 jurors, with six alternates, will remain anonymous and once selected, will be partially sequestered. US Marshals will escort them to and from the federal court every day.
Guzman was seemingly attentive and followed via translation. For the most part, he did not make eye contact with potential jurors, who were brought within about three meters from him for individual questioning.
'Most expensive trial in history'
It is these ordinary men and women who will determine whether Guzman - the diminutive father of two whose nickname means "shorty" - is guilty or not of 11 trafficking, firearms and money laundering charges.
According to the indictment, the Sinaloa cartel, which Guzman is accused of leading from 1989 to 2014, became "the largest drug trafficking organisation in the world... with thousands of members".
US prosecutors contend that from 1989 to 2014, the cartel smuggled at least 340 892 pounds 154,626kg of cocaine into the United States, as well as heroin, methamphetamine and marijuana, raking in $14bn.
Guzman pleads not guilty, but the government has presented so much evidence - more than 300 000 pages and at least 117 000 audio recordings - that the defence complains they haven't had enough time to review it all.
"It's probably set up to be the most expensive trial in the history of the US," said Rob Heroy, a North Carolina lawyer who has defended other Mexican drug barons. But at what price?
The Sinaloa cartel that Guzman founded in 1989 is still hugely powerful. His co-defendant Ismael "El Mayo" Zambada remains at large, and violent drug trafficking continues unabated in Mexico.
Last year, Mexico witnessed a record 29, 000 murders. In the United States, opioid addiction has spiraled into an epidemic. In 2016, an average of 174 Americans died every day from drug overdoses.
At least some of the several hundred witnesses expected to testify are in witness protection programs or are already in jail, housed in special wings to protect them from reprisals.
Even Guzman's lawyers are in the dark as to all the former associates, hired hands or rivals who have turned informants.
Guzman has been held in solitary confinement in New York since Mexico extradited him in January 2017, one day before Donald Trump took office. He spends 23 hours a day in his cell.
The only visitors he is allowed are his lawyers and twin, seven-year-old daughters, from whom he is separated by thick glass.
The judge has banned his 29-year-old beauty queen wife, Emma Coronel, from visiting. As jury selection is being held behind closed doors, she did not attend on Monday.
Arrested for the first time in Guatemala in 1993, El Chapo spent more than seven years in a Mexican prison before his first escape in 2001.
Re-arrested by Mexican marines in February 2014, he escaped again 14 months later.
Guzman was re-captured in January 2016 after a visit from Hollywood actor Sean Penn and a Mexican actress, who wanted to make a film about his life, allowed Mexican authorities to trace his whereabouts.
This time, Mexico decided to wash their hands and put him on a plane.