I-35 is the story of David, a loner in his late 20s from New York City who suffers from blackout migraines and has a penchant for painkillers. He wakes up one morning, freezing in the backseat of his car, 1,500 miles from home, with no idea how he got there. After hearing a horrifying voicemail, he embarks on a harrowing journey through America's heartland, searching for his estranged brother and his brother's wife, while attempting to piece together his own fractured memory. Along the road, David meets a cast of odd characters who become suspects in his clouded and paranoid mind. And just as the clues begin to add up, a chance encounter at a seedy Oklahoma diner leads him to Shawna--a beautiful girl, shrouded in mystery, who escorts him down a vertiginous path to the end of the I-35 highway...where a shocking truth is revealed.