The 18-year-old Holloway was last seen leaving a bar with the three men on May 30, 2005, hours before she was scheduled to board a plane home with high school classmates celebrating their graduation on the Dutch Caribbean island.
Holloway's mother, Beth Holloway, has relentlessly pursued the case, searching for answers about her daughter's disappearance.
"What I know to be true is that Natalee is not on this earth, but I truly believe that I will get answers one day," Beth Holloway said last month on "Good Morning America."
Holloway also said that she feared her chances of finding out what happened to Natalee were fading away.
"I think that, I think that it's certainly not in the forefront anymore," she said.
In fact, authorities in Aruba searched van der Sloot's home in Aruba in April, and ABC News has learned that police questioned his family as recently as last week. Prosecutors say they will continue their investigation until the end of the year, when the statute of limitations runs out.
ABC News' Chris Cuomo spoke with van der Sloot more than a year ago. After initially denying it, van der Sloot admitted to having a romantic encounter with Holloway on the beach, but he insisted he left her alone at the beach.
He has continued to insist he had nothing to do with her disappearance and told Cuomo during the interview he was hoping to put the whole thing behind him.
But van der Sloot said he thinks about that night all the time. "I think about it always, and say, what if, what if. But of course I can't go back and change that."
Feelings among islanders about the long unsolved missing persons case appear to be split between those who are tired of the stain the case has left on the otherwise unblemished reputation of Aruba as a tourist paradise, and those who remain anxious to see the case resolved.
"Some of my friends are saying, 'do they finally have something on these guys?' Danela Colinha, 27, who has lived on the island for two years. "They really want to see this whole problem solved.
"Other people hate [Natalee's mother] Beth Twitty and the media,'' he said.
"But you know what? She's her mother. She's the first person who has the right to know what happened. I understand her rage. I understand why she's so mad,'' Colinha said, pointing out that it's been 30 months since the blonde Alabama teen disappeared without a trace.
"She still doesn't know what happened to her daughter."
The Associated Press contributed to this report.