"This was a horrible crime, but I couldn't understand why immediately Amanda was painted in this horrible light, where she was unrecognizable," said Mellas.
"Amanda is the kindest person I know," Deanna Knox said. "She will do anything to make people happy, and she cares about everyone else before herself."
"20/20" brought in Joe Tacopina, a high-profile New York criminal defense attorney who also has law offices in Italy, to analyze the case, which has been plagued by speculation.
"This case, like many high-profile cases that garner a lot of media attention, is larded with nontruths and rumors that sort of take on a life of their own," he said.
"The prosecution argued that it was a sex game gone wrong, and Patrick Lumumba was involved and Amanda and Raffaele and they all took turns holding her down, while they violated her sexually," he said.
Tacopina was given exclusive access to Italy's top crime lab along with the case files from the prosecution and defense to unravel this mystery.
With three suspects in custody, the prosecutor Giuliano Mignini believed he had found his assailants. But within weeks, Lumumba was released after several people came forward to confirm his alibi and no evidence of him was found at the crime scene.
Police found strong new DNA evidence of another person, Rudy Guede, that didn't match any of their original suspects. However, the prosecutor remained firm in his belief that Knox and Sollecito were involved in Kercher's death, despite their denials of any involvement. He argued that the forensic evidence against the two was still very strong.
Tacopina uncovered records that could be a bombshell for the defense. Records show the DNA match on the knife has less than a 20 percent chance of being connected to Kercher and it is not blood, but rather just a human trace.
"That's not the murder weapon, because if you use that knife as a murder weapon, and as bloody as that crime scene was, you're not going to be able to clean off all the blood, yet leave some other transferable DNA," he said.
Tacopina also says that he learned that additional crime scene photos taken two weeks after the murder showed that "the apartment was rearranged," when compared to the initial crime scene photos.
"The evidence was moved. The bed was leaning up against the wall. … For a crime scene to be worth anything, forensically, it has to be pure and it can't be trampled on, it can't be moved."
Tacopina says this is a "huge blow" to the prosecution's case.
"[There are] countless cases, high profile cases, where the lack of the sanctity of the crime scene has blown the case for the prosecution, starting with O.J. Simpson."
After Lumumba was freed for lack of evidence, prosecutors turned their attention to Guede, who hung out at the basketball court near Kercher and Knox's house. Italy's top forensic lab meticulously matched Guede's palm print to a bloody print on a pillowcase under Kercher's body and identified his DNA inside her.
Guede says he had consensual sexual relations with Kercher the night of her murder. He states that he went to the bathroom and returned to the bedroom to find Kercher alive on the floor with her throat slashed and saw an intruder fleeing the scene. Guede says he put a washcloth on her throat in an attempt to save her, but then left the cottage, fearing for his own life.