Dean walks down a corridor with a gun, then goes into a room with a sign mentioning River Grove on the wall. Several people are there and a man says it's not in him. A doctor is present and says she can't tell for sure. Dean aims the gun, and fires… and Sam wakes up from his vision-dream.
Dean and Sam drive to River Grove while Dean wonders how the dream relates to the yellow-eyed demon. They roll into town and ask an ex-military man, the Sarge, about the man Dean saw in his vision. They get directions to the man, Duane Tanner, and Dean notices the word "Croatoan" carved on a board. Dean notes how a similar word was found at the Roanoke colony in America and it was wiped out overnight. They try to call out but can't get a cell signal and the pay phone is dead.
They go to the Tanner house and talk to Duane's brother Jake and his father, but Duane is on a trip. The two act strange and after Dean and Sam leave, they double back and see Mrs. Tanner tied up in the kitchen as her son and father prepare to cut her and mingle their blood with hers. Mr. Tanner comes at them and they're forced to shoot, and when Sam hesitates, Duane runs into the woods.
The brothers take Mrs. Tanner to the local doctor, Lee, and she tries to explain how her son and husband "had the devil in them." The Winchesters wonder if demon possession is involved, but there was no black smoke. Dean drives to go get help but finds a car with a bullet through the windshield. It's filled with blood and there's a knife nearby, but no bodies.
Dr. Lee examines Mr. Tanner's body and determines he was fighting off some kind of infection. There are also traces of sulphur. On the road, Dean keeps driving and comes to an improvised blockade lead by Jake Tanner. They tell Dean there's a quarantine in place and ask him to get out of the car, and Dean drives off as they open fire.
Dr. Lee tries to take a sample of Mrs. Tanner's blood, but she goes berserk and attacks them, and Sam is forced to knock her out with a fire extinguisher. Dean drives through town and runs into the Sarge from easier. After a tense standoff, they determine they're both unpossessed and head for Dr. Lee's office. Her nurse, Pam insists on going out to find her boyfriend but Sam convinces her to stay. Dean and the Sarge arrive and Sam tells his brother that their father suspected "Croatoan" was the name of a plague-demon. Sarge warns that his neighbors got stronger the longer they were infected, and they have to kill Mrs. Tanner. Dr. Lee doesn't know of any way to cure her and they go in, but Mrs. Tanner is apparently normal. She doesn't' fool the brothers and Dean shoots and kills her.
The group tries to plan a defense when an apparently uninfected Duane arrives. He claims he fought off the other infected people but Dean notices he has a cut and they tie him up. Dr. Lee notices there's no way to determine if he's infected until after he is possessed. Sam warns Dean that his vision is coming true and that his brother is acting increasingly violent. Dean locks Sam up and then goes to shoot Duane. Dean considers it but in the end can't bring himself to do it. He lets Sam out and they prepare explosives from the medical supplies. Dr. Lee has had enough time to determine Duane is clean and they untie him. Pamela manages to get Sam alone for a minute… and attacks him, mixing her blood with his through a cut. Dean shoots and kills her, but Sam is now infected.
Dean refuses to shoot Sam but Sam offers to kill himself. Dean still refuses and gives them the Impala keys so they can escape. After they leave, Dean admits he's tired of the job and starts to talk about John, but Dr. Lee returns and interrupts them. It's night outside and everyone has vanished. Five hours pass and Dr. Lee determines that Sam's blood is clear. Lee checks the Tanner samples and determines there's no trace of the virus. Duane and Sarge head south while Sam wonders why he was immune. Later on the road, Duane asks the Sarge to pull over to make a call, then cuts the Sarge's throat and collects his blood in a familiar goblet. Duane reports that no further tests are necessary and Sam is immune as they suspected.
Later Sam and Dean take a break and Sam insists that Dean tell him what he was going to say before he was interrupted. Dean says that he promised John not to say anything but says that John told him something about Sam…