Both have already denied any wrongdoing over the meltdown, which sent markets into a tailspin.
Lawmakers accused accountants and company chiefs of setting up a secret network of companies and schemes to overstate profits and hide billions of dollars of debt that Enron could not pay off.
Mr Lay entered the courthouse holding hands with his wife Linda, accompanied by his defence team. He made no comment.
The founder of Enron, Mr Lay, served time as chairman and chief executive. He faces seven counts of fraud and conspiracy.
His colleague, Mr Skilling, entered the court with his lawyer Daniel Petrocelli.
Asked how he was feeling ahead of the trial, Mr Skilling said, "fine."
Mr Skilling, who served several months as chief executive, faces 31 charges of fraud, conspiracy, insider trading and lying to auditors about Enron's financial position.
The two men are likely to argue they were simply following the advice of their accountants and lawyers.
Some other Enron executives have already pleaded guilty and been sentenced to jail. Some are helping prosecutors in their cases against Mr Lay and Mr Skilling.
Four month trial
Judge Sim Lake said he hoped the complex trial would be finished in about four months.
Jury selection is expected to be completed by Monday.
"I can assure those of you selected that this will be one of the most interesting and important cases ever tried," Judge Lake said as he started the selection of the panel.
Test for prosecutors
The trial also presents a huge test for the special US Justice Department task force set up after scandals at Enron, WorldCom and other companies to crack down on corporate misdeeds.
Enron collapsed in 2001 sparking estimated losses of over 40 billion dollars, and triggering the rapid downfall of its auditor Arthur Andersen.
It’s implosion sparked panic on Wall Street over what was then the biggest corporate meltdown in history.