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.
The plane had 14,500 flight hours, "consistent with aircraft of that age," Bornhorst said.
The University of Kentucky hospital was treating one survivor, who was in critical condition, spokesman Jay Blanton said. No other survivors have been brought to the hospital, he said.
Fayette County Coroner Gary Ginn said the passengers and crew appeared to still be on the plane and the deaths were caused either by the impact or the "hot fire" on board.
"We are going to say a mass prayer before we begin the work of removing the bodies," Ginn said, referring to the chaplains who serve the airport.
A temporary morgue was being set up at the scene and the bodies will be brought to the state medical examiner's office in Frankfort, Ginn said.
He said both flight recorders have been found.
Rose Wilson, who lives near the airport, said she was awakened by the crash.
"I thought it was thunder," she said.
Investigators from the FAA and the National Transportation Safety Board were en route to the scene, said Brown of the FAA.
The airport closed for three hours after the crash, but reopened by 9 a.m.
Chaplains at Hartsfield Jackson Atlanta International Airport were meeting with family members waiting for their loved ones at the airport, said the Rev. Harold Boyce, an airport chaplain.
White House spokeswoman Dana Perino said President Bush, who is spending a long weekend at his family's summer home on the Maine coast, was being briefed on the crash by aides. The news of it broke while he and his wife, Laura, where at church with the elder Bushes. Perino had no other information about the crash.
Comair is a subsidiary of Delta Air Lines based in the Cincinnati suburb of Erlanger, Ky.
The Bombardier Canadair CRJ-100 is a twin-engine aircraft that can carry up to 50 passengers, according to Delta's Web site.
There has not been a major crash in the United States since Nov. 12, 2001, when American Airlines Flight 587 plunged into a residential neighborhood in Queens, N.Y., killing 265 people, including five on the ground.
On Jan. 8, 2003, an Air Midwest commuter plane crashed on takeoff at Charlotte/Douglas International Airport, killing all 21 aboard.
Last December, a seaplane operated by Chalk's Ocean Airways crashed off Miami Beach when its right wing separated from the fuselage shortly after takeoff, killing the 18 passengers and two crew members. That plane, a Grumman G-73 Turbo Mallard, was built in 1947 and modified significantly in 1979.
The NTSB's last record of a CRJ crash was on November 21, 2004, when a China Eastern-Yunnan Airlines Bombardier crashed shortly after takeoff. The 6 crew members and 47 passengers on the CRJ-200 were killed, and there were two fatalities on the ground.