Dean struggles with the after effects of the Mark of Cain. Meanwhile, Sam hears about a case where straight-laced people are turning into unhappy murderers. Sam suspects possession and suggests to Dean that they investigate, but Dean tells him to go without him. While interviewing the local townsfolk, Sam meets an elderly woman named Julia, who tells him the Men of Letters came to town in 1958. Josie tells Sam the story of a young man named Henry Winchester and his female companion, Josie Sands. While Sam is away, Crowley tests Dean.
Sam Winchester is a college student bound for law school, determined to escape his family's past - unlike his older brother, Dean. Ever since they were little their father has been consumed with an obsession to find the evil forces that murdered his beloved wife, and recruited his two young sons to help them. They have grown up as hunters of the supernatural. Sam escaped this way of life after high school, and now has a happy life with his girlfriend, Jessica, and a promising future career. Dean, however, stayed behind with his father to join him in his "hunting".
After Dean arrives for Sam's help when their father goes missing, Sam must join his brother to find him. His one weekend trip to search for the missing John Winchester becomes an ongoing quest after a horrible tragedy ruins any thought of a happy life for Sam.
The two brothers, bound by tragedy and blood to their mission, travel across the country encountering terrifying and dangerous forces most believe to be nothing but superstition and folklore, such as the Lady in White, the Indian beast known as the Wendigo, Phantom Travelers who cause plane crashes, Bloody Mary, and many more.