Sam Winchester (Jared Padalecki, Gilmore Girls ) has done his best to escape his family's eerie history. Unlike his older brother Dean (Jensen Ackles, Smallville ), Sam rejected their father's obsessive quest to uncover the evil forces that claimed the life of the boys' mother, Mary (guest star Samantha Smith). Putting as much distance as possible between himself and his family, Sam left home right after high school and went away to college. His new life includes a beautiful and loving girlfriend, Jessica (guest star Adrianne Palicki), and plans to enter law school. Dean, however, took a very different path, following their father, John (Jeffrey Dean Morgan, Weeds ), into the "family business." When Dean arrives on Sam's doorstep with the news that their father has vanished, Sam has no choice but to put his personal plans on hold and join Dean on the road.

After four years apart, the reunited brothers are getting to know one another again, and their familiar sibling rivalries are never far from the surface. Despite the strange childhood they shared, these boys turned out to have very different views of the world. Dean still idolizes John and, although he often appears cocky and fearless, in reality he is haunted by memories of his mother's violent death. Sam was too young to remember the awful night that Mary died and has never fully accepted the frightening path his father and brother have followed.

A mysterious phone message from their father leads the Winchester brothers to a California town plagued by a series of unexplained deaths. They soon come face-to-face with the local legend of a Lady in White - a ghostly and beautiful hitchhiker who wanders country roads by night, luring young men to their doom. Though they don't find their father, Dean and Sam discover his journal and try to decipher his writings for clues that will help them destroy the spirit.

Bound by tragedy and blood to their dangerous, other-worldly mission, the brothers travel from the Colorado wilderness to Nebraska farmlands and on to isolated Wisconsin lakes, encountering creatures that most people believe only exist in folklore, superstition and nightmares - the terrifying Bloody Mary, the brutal Native American beast known as the Wendigo, the man with a hook who haunts Lovers' Lanes and the dark Phantom Travelers who portend a violent plane crash. As they follow the clues in their father's journal, the brothers realize that he has passed on to them all the knowledge he accumulated during the past 20 years. What they can't understand is why he has vanished and left them to carry on without him. Taking up the mantle of their father's crusade, Dean and Sam hunt down the evil that preys upon the innocent in the darkest corners of America.

Crisscrossing the lonely and mysterious back roads of the country in their '67 Chevy Impala, the Winchester brothers search desperately for their missing father - and hunt down every evil supernatural force they encounter along the way