Mollie Tibbetts, 20, was last seen in the town of Brooklyn, 50 miles west of Iowa City on Wednesday evening.
Family members told WOI-TV that the University of Iowa student was dog-sitting with her boyfriend at a house before she went for a run.
Relatives said the last contact they had with her was at 10pm through Snapchat.
They knew something was wrong when she failed to show up for work the next day.
“This is not like her at all,” said her aunt Kim Calderwood.
“She’s a very responsible and conscientious young woman.”
Tibbetts’s boyfriend, Dalton Jack, told ABC News she went for a run around 10pm.
He said: “She might have a FitBit on and she might have her cellphone, but obviously we’ve tried just calling her but it’s either off or dead so it would go straight to voicemail.”
Poweshiek county sheriff Thomas Kriegel said: “Everything’s on the table, unfortunately.
“We’re hoping that she’s somewhere with a friend and she’ll show up Monday or Tuesday and everything will get back to normal.”
The search, which includes using a helicopter, has focused on barns, dirt roads and fields between Tibbetts’s house and where she was staying when she was last seen.
Investigators are working with the university to access a laptop and online accounts belonging to Tibbetts that may have an electronic footprint of her whereabouts, said her cousin Emily Heaston.
“It can be slow and frustrating, but it is our best hope of securing Mollie’s location,” she wrote on Facebook.
Tibbetts is described as 5ft 2in tall, weighs about eight-and-a-half stone, and has brown hair and brown eyes.
She was last seen wearing gym shorts, a black sports bra and running shoes.