Zahra and Salma Halane, from Manchester, were described by neighbors as "nice girls" from a "very religious family."
The North West Counter Terrorism Unit is investigating.
"At this stage we don't know for sure where they are or exactly who they are with," Detective Chief Superintendent Tony Mole said.
"They are clearly posing a threat to themselves and potentially the community and their family and friends are concerned for their well-being."
The safety of the teens, Mole said, "is our overarching priority."
To date, approximately 500 British Muslims are believed to have traveled to Syria to fight. Imams in Britain have urged British Muslims not to travel to Syria and Iraq.