Forty-nine of the 50 people aboard were killed. The one survivor, a crewmember, was reported in critical condition.
U.S. officials who requested anonymity told CBS News Correspondent Bob Orr that the pilots apparently used a runway that was too short to accommodate the takeoff of the jet.
The officials said the pilots had made "a critical and fatal mistake."
The plane, Comair Flight 5191, a CRJ-200 regional jet with 47 passengers and three crew members, crashed at 6:07 a.m. Sunday after taking off for Atlanta, said Kathleen Bergen, a spokeswoman for the Federal Aviation Administration.
a newlywed couple starting their honeymoon and a man who took an early flight to get home to his children. Jon Hooker had just married Scarlett Parlsey the night before the crash in a ceremony with 300 friends and relatives at Lexington's Headley-Whitley Museum.
The plane was largely intact afterward, but there was a fire following the impact, police said.
A little after 6 a.m., flight controllers gave the pilots clearance to take off from runway 22 and the pilots acknowledged the controllers with a "roger," Orr reports. However, it appears the pilots took off from runway 26, which is only half the size of the 7,000 foot runway 22.
Sources tell Orr the radar tape and debris from the crash site suggest the plane never got airborne, that instead it went off the end of the runway and through a retaining area before settling into the crash site where it seems a significant post-crash fire erupted.
Orr adds that two flights took off from the correct runway (22) just prior to the Comair flight's departure.
Comair President Don Bornhorst confirmed the number of passengers, but gave very few details of the incident during a press conference Sunday morning. He urged victims' relatives to call (800) 801-0088 for more information.
"We are absolutely, totally committed to doing everything humanly possible to determine the cause of this accident," Bornhorst said at a news conference.
He said he could not speculate on the cause or confirm who the survivor was.
"We have no indication at all that this has anything to do with terrorism," said Laura Brown, an FAA spokeswoman.
The crash marks the end of what has been called the "safest period in aviation history" in the United States.
Lexington police spokesman Sean Lawson said investigators were looking into whether the plane took off from the wrong runway.
"The crew had been operating the same airplane for quite some time," Bornhorst said.
The pilot was hired in 1999 and had been a captain since 2004. The First office had been with Comair since 2002, and the flight attendant had been with Comair since 2004.
Bornhorst said the maintenance of the plane was up to date, with routine maintenance as recently as Saturday. Comair purchased that plane in January 2001, and all maintainance was normal as far as the information Comair has now, he said.