The Winchesters encounter the mysterious and very much still alive Doc Benton when they look into a series of abductions where the victims report missing body parts after forced surgery. When Bobby manages to locate Bela, Dean heads off to confront her and get the Colt back. Meanwhile Sam stays behind hoping that Doc Benton can make Dean immortal to get him out of the Deal.
Dean's time is up and he has to pay the Devil his due. When Lilith resurfaces in New Harmony, Indiana terrorizing a family to no end Sam, Dean, and Bobby steal Ruby's knife and confront the mother of all demons in a battle to the death.
Sam tries to move on without his brother and becomes hardened and more reckless in the way he hunts. Bobby and his psychic friend Pamela try to contact the other side to find out more about Dean's ultimate fate.
Castiel sends Dean back in time to 1973 where he encounters younger versions of his parents and for the first time meets his grandfather Samuel Campbell who holds a secret that sheds a light on the Winchester Family's connection to the hunter community.
A hunter named Travis points Sam and Dean towards a meat eating creature called a Rugaru. Complicating matters is the fact that Travis's target is a normal suburban dad in the earlier process of changing and he hasn't killed anyone yet.
Sam and Dean discover a Colorado small town's darkest secret as a wave of people fall prey to a "ghost sickness" that induces fear, paranoia, and ultimately a fatal heart attack. Sam and Bobby must figure out the cause and cure of the sickness when Dean himself falls prey to it.
Sam, Dean, and Ruby discover the existence of a female prophet named Anna Milton, who can hear the voices of angels and thus figures into the plans of a demon named Alastair who wants to use her as a tool against the angels.
Dean and Sam figure out why Castiel and his superior/handler, Uriel the Angel of Death, want Anna Milton dead when the three of them are forced to go on the run, not only from heavenly and vengeful angels, but from Alastair and his demon minions who also try to track down Sam, Dean, and Anna. With the assistance from the now-blind soothsayer, Pamela Barnes, they discover that 'Anna' is a fallen (former) angel and needs to seek her grace wings before the forces of both Heaven and Hell find them.