Knox was convicted last December along with her former boyfriend Raffaele Sollecito, 25, of sexually assaulting Kercher and then killing her by slashing her throat.
Sollecito, who is also appealing his case, was sentenced to 25 years in prison. A third person convicted of taking part in the murder was Ivory Coast native Rudy Guede. He was convicted in a separate trial and sentenced to 30 years in prison, but that term was reduced to 16 years on appeal.
Knox has spent the last three years in a 129 square foot prison cell in the outskirts of Perugia, Italy.
"The long pre-emptive custody has broken down the young woman," Knox's lawyers said in a motion filed earlier this month as part of their appeal. Ghirga described Knox as "worried, tense" ahead of the appeal, and "exhausted by three years in prison."
"Amanda says prison is like not living because nothing changes. She says everything is the same incessantly," her stepfather Chris Mellas told ABC News earlier this month.
Her family said that Knox has had trouble sleeping as the appeal date approached. She was apprehensive, but hopeful, they said.
Key to Knox's appeal is her legal team's request that the prosecution's forensic evidence be reviewed independently. They are challenging whether Kercher's DNA was found a knife from Sollecito's kitchen, and whether police properly collected evidence, particularly a bra clasp which contained Sollecito's DNA.
The defense will also attack the prosecution's shifting version of a motive for the killing which ranged from a sex game gone wrong to a personal feud over Knox's boyfriends and hygiene.
In the appeal, Knox's lawyers said "the motive, a fundamental aspect of a serious crime, is basically absent."
Her defense team was also encouraged by a written conclusion of the case by Judge Giancarlo Massei appears to contradict the prosecution's argument that Kercher's murder was the result of Knox's explosive rage at her "prissy" roommate who complained about Knox's hygiene and for bringing male friends to their Perugia apartment late at night.
Prosecutors claimed during the trial the assault was initiated by Knox, but the judge wrote that Kercher's death had an "erotic, sexual, violent" motive that was initiated by Guede "giving in to his lust." When Kercher turned him down, Knox and Sollecito joined in the effort to overpower Kercher because it "could have seemed particularly exciting," the report states.
According to the report by Massei and his assistant judge, the murder was not planned or premeditated and not the result of resentment of the part of Knox or Sollecito towards Kercher, as the prosecutor had maintained.
The appeal will be considered by a jury of two judges and six jurors.
"It's a real second chance," criminal defense attorney Alessandra Batassa told ABC News. "You can ask in your appeal for new evidence, new witnesses and you can try to demonstrate you are innocent one more time."
Chris Mellas said Knox's days involve reading, an hour she is allowed to exercise and some socialization time in the afternoon when her prison door is unlocked and she can mingle with other prisoners. They often play cards or just talk among themselves.
"Once a week they have choir. Amanda is singing in the Christmas show this year. She is singing soprano – in Italian," he said.
Knox is a voracious reader and recently she has taken up art.
"Amanda is doing a lot more art. She is a talented artist. She only has access to colored pencils, markers and paper. She is doing a lot of drawings of the family and sending them to us," said her mother Edda Mellas.
Knox has received permission to continue her studies and is taking classes through the University of Washington in creative writing. She hopes to complete her college degree in English.