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John Winchester's wife Mary was just killed by a demon in the nursey of their youngest son Sam. John obsesses and can't seem to pick his life up where he should. Instead, he flees with the boys to enter into a life of tracking down the demon that killed Mary. The boys start out very young: Dean around age 4 and Sam just a baby. By the end of issue, years have passed and Dean is 10 and Sam is 6.
Issue #1 is where John seeks advice from Missouri Mosley and begins his days of magic. She rips one of his fingernails for a spell and has a vision of danger occurring in a house. The house matches the description of Mary's best friend Julie who was charged with watching the boys for the night. John and Missouri arrive at the house too to save Julie but the boys are okay. At that moment, John realizes they won't be safe with anyone but him and the boys will have to learn how to survive, hunt and kill. Before their journey takes them out of Kansas, Missouri gives John the fang from a Hellhound and tells him to find Fletcher Gable in Eureka.