After learning of the state of Heaven and the fact that the archangels were either dead or imprisoned, the Scribe of God Metatron enacted a plan to get revenge on the angels by casting a spell to make them Fall. To this end, Metatron tricked the Seraphim Castiel into helping him get the needed ingredients for the spell in the guise of the Angel Trials. Thanks to Castiel, Metatron got the needed ingredients and cast the angels from Heaven, trapping them on Earth. In the process, Metatron stole Castiel's grace as the last ingredient in his spell, rendering him human. Due to the angels hunting Castiel, Gadreel forced Dean to eject Castiel from the bunker as the angels would be hunting him and it wouldn't be safe for Gadreel.
After Falling to Earth, the Rit Zien Ephraim managed to find a vessel in the form of a recently religious man who had recently begun following the Reverend Buddy Boyle who Bartholomew and his faction were using to recruit vessels. However, Ephraim had never been to Earth before or had a vessel so he was confused by emotional pain and came to believe that he had to cleanse the Earth of it which involved killing those in great emotional pain.
Ephraim began his self-appointed mission by smiting his vessel's wife and proceeded to kill two other people, including a suicidal man and leaving nothing behind but a pink substance due to the nature of his brand of smiting. The "disappearances" of Ephraim's victims made the headlines of the local newspaper and drew the attention of the former angel Castiel who was working at a nearby convenience store.
After seeing the headlines, Castiel called Dean for help telling him about the missing, presumed dead victims who had a strange substance left behind at the scenes of their disappearances. Bored with research on how to translate the angel tablet, Dean decides to check out the case and heads to Rexford, Idaho.
In Rexford, Dean goes to the latest victim's cabin where the sheriff informs him that they now have confirmation that the four victims are dead. The sheriff shows Dean the pink substance coating the victim's cabin and tells him that tests show that its everything of the victim down to their clothes and that the neighbors reported a pink flash when it happened. Dean scans the crime scene for EMF, sulfur and hex bags, but is unable to locate anything.
After a teenage girl gets dumped by her boyfriend in front of the entire cafeteria, Ephraim kills her too, not knowing that her emotional pain was something she'd get over and wasn't permanent like his other victims were.
After seeing the crime scene, Dean visits Castiel at his job and speaks with him about what he's been doing now that he's a human. As they talk, Dean gets a call about the murdered girl and convinces Castiel to join him in checking it out despite Castiel's lack of powers. As Dean talks to the victim's friend, Castiel sees the pink spray and recognizes it as the work of a Rit Zien. Castiel tells Dean about how the Rit Zien healed angels that could be healed but also put down those that were beyond saving. Castiel explains how when Ephraim arrived on Earth he would've homed in on his victims pain, but not knowing the difference between emotional and physical pain, would've set out to eliminate all human suffering. While Dean sets out to find and stop Ephraim, Castiel chooses not to join him due to his newly-human status and instead has Dean drop him off at what he believes to be a date at his boss Nora's house.
As Dean leaves Castiel, he gets a call from the local sheriff who tells him that the DNA tests on the remains of the married couple only came back with the wife's DNA meaning that the husband was still out there somewhere. Dean goes to the sheriff's station where the sheriff goes over the history of the married couple, including how the husband had become obsessed with Reverend Buddy Boyle. Dean realizes that the husband is missing as he's the angel's vessel and sees a picture of the man's truck and remembers seeing outside of Nora's house when he dropped Castiel off. Dean realizes that the angel is after Castiel and quickly rushes off to rescue him.
At Nora's house, her daughter Tanya gets a fever and Castiel, growing worried, goes to take her to the hospital only to find Ephraim at the door. Ephraim is surprised when Castiel recognizes him, explaining that while Casitel has been on Earth before, he never has and he finds the experience to be intense. Though Castiel tries to get Ephraim to stop what he's doing, Ephraim tells him he doesn't intend to stop until he cleanses the planet of all suffering. When Ephraim steps towards a crying Tanya, Castiel intervenes, believing that Ephraim has sensed the pain Tanya is in from her fever and is going to kill her. However, to Castiel's surprise, Ephraim tells him that he's not there for Tanya, he's there for Castiel. As Castiel cuts his thumb on a rose and uses his blood to draw an angel banishing sigil, Ephraim explains that he could feel Castiel's pain at being human for miles and tracked him through that despite his tattoo. While Castiel insists that the humans in pain can get better and are just doing the best that they can, Ephraim tells him that if what Castiel is doing is the best he can, than Castiel is a more urgent case than he thought. Ephraim notices the banishing sigil Castiel is drawing and grabs his hand and twists it, stopping him from completing the sigil.
Ephraim prepares to smite Castiel, telling him he'll take Castiel's pain away. When Castiel insists that he wants to live, Ephraim asks if he wants to live as an angel or a man. Before Ephraim can smite Castiel, Dean rushes in armed with an angel blade, but Ephraim flings him across the room before Dean can reach him. Ephraim tells Castiel that while Castiel wants to live, Ephraim believes that Castiel choosing a human life means he's given up. As Ephraim starts to smite Castiel, Dean slides Castiel his angel blade. Castiel stabs Ephraim with the angel blade, killing him before he can kill Castiel.
Dean and Castiel clean up Nora's house before she can return and Castiel is able to treat Tanya's fever with acetaminophen on Dean's suggestion. While Dean learns from Sam that the spell that cast the angels out of Heaven is irreversible, he decides not to tell Castiel who is disturbed by what Ephraim told him about how the angels need help and its not right for him to sit it all out. However, Dean tells Castiel that as he's human, dealing with the angel problem isn't up to Castiel anymore and Dean and Sam will handle it. However, Castiel remains disturbed by his inaction, especially after seeing a news report on the Fall.
Castiel eventually leaves his job and sets out to restore the angels to their rightful place in Heaven. After getting in the middle of an escalating confrontation between Bartholomew and Malachi, Castiel steals the grace of the angel Theo and becomes an angel again.