Vicky Glass, 21, was last seen being dropped off by a taxi driver at 4am on September 24, 2000 in Middlesborough.
Her body was discovered in a stream in the village of Danby, near Whitby, six weeks later.
Four people have since been arrested in connection with Vicky’s murder, but all have been released without charge.
Cleveland Police has reviewed the case and now a new team from the Historical Investigation Unit, led by Detective Chief Inspector Peter Carr, has been formed.
On the 21st anniversary of her last sighting, Cleveland Police said the team "will actively reinvestigate her death using new forensic techniques".
Officers also plan to speak to potential witnesses and examine more than 2,000 hours of CCTV footage.
'Been through turmoil'
Ms Glass was much-loved by her family and had a happy childhood. Detectives said her life changed when she was 18 and she was exploited by others who led her into drugs and pressured her into sex work.
It was while she was doing this on the streets of Middlesbrough that she was murdered and police are still keen to find out who she had been with that night.
A website has been launched to appeal for information and to put the case back in the spotlight.
Detective Chief Inspector Peter Carr said: "Much work has been carried out over the last twelve months on Vicky’s case, including a detailed review of the original investigation.
"This review identified over 300 recommendations, with the main one being that a reinvestigation should be undertaken.
"We believe that there are a number of lines of inquiry which can be pursued and by using modern investigative and forensic techniques, we hope to get justice for Vicky and her family.
"We have new and significant lines of inquiry and will be speaking to people connected to the case and trawling through CCTV from the time period to help us with any new leads."
In a statement, Ms Glass' family said they felt her loss "every day" and appealed for information to give them "some hope of healing".
"She deserves justice and hope that this reinvestigation puts those responsible behind bars.
"Vicky was loved deeply by us, and as a family we have been through turmoil especially as mam Deborah passed away without any answers, knowing Vicky’s killer is out there and people have information that they are not coming forward with."
Anyone with information can call the investigation team directly on 01642 301773, Cleveland Police on 101 or Crimestoppers anonymously on 0800 555 111.