The new leads, described as very significant by police, are featured in a 25 minute long British televised appeal for more witnesses and information. The video includes new interviews with Madeleine's parents and a reconstruction by actors of the events leading up to her disappearance.
Police have also raised the possibility that a burglar may have entered the family's vacation apartment in the resort town of Praia da Luz.
Madeleine was 3 when she went missing on May 3, 2007, while her parents dined with friends less than 200 feet away at a restaurant inside a hotel resort. What happened to her remains a mystery.
The case was closed by Portuguese police in 2008, but Scotland Yard launched its own review in 2011, followed by a fresh investigation in July this year. It says it now has a more accurate account of what happened the night Madeleine went missing, which has given new significance to sightings of people in and around Praia da Luz, including the men detectives are now trying to trace.
The focus of previous investigations had centered on a man seen walking away from the crime scene with a child in his arms. British detectives now believe they have identified that man, and have ruled him out of their enquiries.
Detective Chief Inspector Andy Redwood, who is leading the investigation, calls the developments a "revelation." His officers are now focusing on a later sighting of a different man. Witnesses saw the man walking away from the apartment carrying a small child at around the same time Madeleine's mother discovered she was missing.
"It is vital that we identify who he is," Redwood said. "The description of two different witnesses who saw him said he was a white man aged in his 30's with short brown hair, medium build, of medium height and clean-shaven. He was seen carrying a child aged 3-4 years old who had blonde hair and was possibly wearing pajamas. There may be an entirely innocent explanation of this man but we need to establish who he is to assist with our enquiries."
Police have also appealed for information on a number of unidentified "blonde-haired" men seen near the McCann's apartment on or around May 3, 2007. According to Scotland Yard, they may have been scoping out the family's routine and planning to abduct Madeleine. Some eyewitnesses have said the men looked Scandinavian, and were possibly speaking in German or Dutch.
A surge in the number of burglaries in the area around the time of Madeleine's disappearance, including in the same block of apartments, may also be significant. In addition, Scotland Yard are looking at what might have been a number of con men posing as charity workers collecting donations from vacationers in the area.
Detectives describe the new leads as significant, but believe there's still a long way to go in their investigation.
Madeleine's parents, Kate and Gerry McCann, have spoken about the events of the day that she went missing, and how they felt "upset, angry" when there were made suspects by Portuguese police.
Kate McCann has described the moment she realized Madeleine was no longer in the apartment.
"I guess I was looking at Madeleine's bed and I couldn't ...couldn't make it out, and I realized that she was not actually in that bed and I thought ahh...I wonder if she has woken up and gone through to our bed...She wasn't in our bed and that was the first time where I guess panic kicked in."
"When it's a special occasion, when you should be your happiest and Madeleine's not there, that's when it really hits home," Gerry McCann said in the televised appeal.
Praia da Luz is a popular vacation destination, so detectives are travelling to Holland, Germany, and Ireland to appeal for more information. The British TV appeal will also be shown in Holland and Germany, where most of the tourists in Praia da Luz come from.
Law enforcement agencies in 30 other mostly European countries have been asked for help in tracing people. British police are offering a $32,000 reward for information that leads to an arrest and prosecution. Data from phone calls made in the area are still being analyzed by police. According to Scotland Yard, phone records were not looked at in detail during the initial Portuguese investigation.
Prime Minister David Cameron has voiced his support for the investigation. "I'm very pleased that Scotland Yard are doing this work," he said. "The Government has helped to fund the work that is being done. This was a crime that touched the heart of everyone in the country and everyone would like to see it resolved, so I hope Scotland Yard continue with their work and I wish them success."
Paul Luckman, publisher of 'The Portugal News', the largest English language paper in the country, is not so sure. "Six years have gone by and the case is over," he tells ABC News. "What can anyone realistically expect to find new?"