In Sanctum, a photograph of the original Simone and her family is shown hanging on a wall.
In Red Sun Rising, Simone is shown in a flashback with the rest of the Mission Team Alpha. In the flashback, she brings her daughter Josephine to see her husband and she gets upset with her daughter for making the children eat an unknown berry that tastes like cotton candy. She then takes a first aid bag and goes to check on the kids. Later Josephine and Gabriel Santiago return to the camp after hearing a sonic anomaly and they find Simone running out of the tent screaming and bleeding. She then dies in Josephine's arms.
In The Children of Gabriel, the current "reincarnation" of Simone is among the first Sanctum Citizens to find Clarke Griffin's group from Earth. When she notices Rose talking to Clarke, she asks her to stay away, saying that they must protect the host. Simone introduces her husband as Russell Lightbourne VII and tells Clarke to bow before saying his name. Unlike Russell, Simone is strict and unwelcoming to the earthlings. When her husband invites Clarke for dinner to discuss if they should stay, Simone is particularly hard on Clarke. She starts asking Clarke about how many people she killed. Simone reveals that she knows Clarke is called Wanheda, which Clarke deduces is from Jordan Green telling Delilah about her past. Simone and her husband decide not to let Clarke's people stay in Sanctum. However, after Clarke rescues Delilah kidnapped by the Children of Gabriel and they discover Clarke has Royal Blood, they change their mind.
In The Face Behind the Glass, Simone becomes suspicious that one of their people in Sanctum is a traitor and a spy for the Children of Gabriel. Her suspicions are confirmed true when they find out that Cillian has paralyzed Clarke because she has royal blood. After learning that Rose has been killed, Simone and Russell come up with a plan to use Clarke as the host for their daughter, Josephine. Russell feels sorry for taking advantage of Clarke while she's paralyzed but Simone convinces him that it was meant to be - it's fate that a host like Clarke landed in Sanctum when she did. To bring Josephine back, they agree to erase Clarke's mind and replace her memories and personality with those of Josephine. So, she opens up her necklace, revealing a Mind Drive, an implant similar to Becca's A.L.I.E. 2.0. She injects Clarke with sedative to knock her out after which they take her to a lab and insert Josephine's Mind Drive inside her. A while later, Josephine wakes up inside Clarke's body. Simone is thrilled to be reunited with her daughter.
In The Old Man and the Anomaly, Simone arrives to the Eligius IV with Abby, Raven and some other Sanctum Citizens. She has convinced a man named Gavin to sacrifice himself to be Kane's host. After figuring out what they are up to, Raven confronts Abby about it. However, Simone says that it is not murder if they volunteer. Before Raven can talk Gavin out of it, Simone injects him with a substance that knocks him out and wipes his mind.
After a spacewalk, Abby's plan to make Nightblood and bring Kane back is a success. Simone take the serum and glad to see that this has worked. She leaves the room to give Abby and Kane and his new body privacy for their reunion.
In What You Take With You, the resurrected Kane is less than pleased by his new state, particularly after he meets Gavin's wife amongst Simone's guard. Kane becomes angry when he realizes that the Primes have been lying about what happens to their hosts and yells at Simone in front of everyone.
Later, Simone prepares to return to Sanctum with the Nightblood when Indra, Niylah and some Sky People enter and take over the dropship at gunpoint, threatening to shoot Simone if her guards try anything. Indra has Simone and the group from Sanctum held captive and orders that if anyone tries to leave, they are to kill Simone. Indra's group takes the Nightblood which is floated alongside Kane at his own request so as to prevent the Primes from creating new Nightbloods.
In Matryoshka, Simone returns to Sanctum with Abby and Raven is disconcerted to see armed guards all over the place. Abby and Raven are arrested and Simone cruelly tells Abby that her daughter is dead after revealing that Kane killed himself and took his Mind Drive with him. After learning what has happened on Sanctum, Simone pushes Russell to execute the prisoners though Russell is far less enthusiastic about the idea, still desiring peace. Simone agrees to execute only one person instead.
Later, the four surviving Primes sit down to lunch where Ryker expresses discontent with the idea of executing someone and Priya strongly rebukes Russell and Simone for acting without consulting the other Primes. Sanctum guards bring the news that Gaia has been captured and a man named Ty who claims to have information on where Echo can be found. Ty angrily confronts the Primes over their actions, including the loss of his child to the Offering Grove due to Josephine's edicts. When Ty expresses hope for Josephine to die too, Simone moves to angrily confront Ty. Shattering a drinking glass, Ty stabs Simone in the throat with a shard of broken glass and is quickly restrained as Russell tends to the dying Simone. Simone dies in Russell's arms and he promises to bring her back again no matter what it takes.
In Ashes to Ashes, Russell has Ryker transform Echo into a Nightblood so that she can become Simone's new host. This plan is foiled when Gaia and Nathan Miller rescue Echo who kills Ryker. Later, when Clarke returns to Sanctum posing as Josephine, she asks Russell about Simone. Russell shows Clarke Simone's Mind Drive and states that there had been an incident. Clarke's arrival prevents Russell from checking on Ryker's progress and thus discovering his death and failure to secure Echo as Simone's new host.
In Adjustment Protocol, Simone is resurrected in the body of Abigail Griffin to the shock and horror of Clarke. Simone mistakes Clarke's sadness as being over Gabriel's betrayal of Josephine and Clarke calling her Mom as Josephine doing it. Simone reveals that they are retreating to space as Sanctum is currently lost to them. Simone threatens Madi's life to force Raven to agree to pilot the Primes and their guards to Eligius IV. When the Primes arrive on Eligius IV, Simone holds Raven at gunpoint to force the surrender of the crew.
In The Blood of Sanctum, the Primes succeed in taking control of Eligius IV using their hostages. However, Sheidheda uses Madi to order Wonkru to attack, leading to several being shot by Sanctum guards. Russell announces his intention to take the Primes to Planet Beta and for them to return to their past as explorers to find a new home. Simone pushes Russell to kill Madi due to the danger she poses to them, but both Russell and Clarke refuse. Simone agrees, but insists that they must kill Wonkru in their sleep to prevent them from being awakened to use against the Primes, the Primes having brought enough mind wiping fluid to erase Wonkru in their sleep where they will be perfectly preserved until the Primes need new hosts. The other Primes agree with Clarke, as Josephine, pretending to be unbothered by the idea.
As Simone and Russell prepare to begin the mind wipe, Clarke tries to talk them out of it without breaking her cover, pointing out that the sleeping people represent the remainder of the human race. Simone notes that "Josephine" sounds like Russell, but is unmoved and asks for the serum. Desperate to see if Abby still survives, Clarke asks Simone about her symptoms before explaining how Abby would've had a neural mesh too. Russell assures Clarke that Abby really is gone, having checked her for a neural mesh before resurrecting Simone as he didn't want to make the same mistake twice. Clarke refuses and raises a gun at the Lightbourne's who realize the truth. Clarke walks away with the serum, telling Josephine's devastated parents that she can't let them kill all of those people and she really is sorry for their loss. Simone orders the devastated Russell to get Madi to use as leverage while she collects the other Primes to track Clarke through her Mind Drive.
Accompanied by Caleb, Jasmine and Miranda, Simone tracks Clarke to the Eligius IV airlock where she threatens to blow them all out into space if they don't surrender. Simone suddenly grabs a gun and turns on the other Primes, claiming to Clarke that she is Abby who survived the implantation of the Mind Drive. However, Clarke asks "Abby" to identify her father. Unable to, Simone turns her gun on Clarke who activates the airlock, floating all of the other Primes. Simone manages to hang onto Clarke who strapped herself to the wall, but after staring at Simone for a moment, Clarke shoves Simone off of her. Simone is blown into space, killing her. A devastated Russell watches from the bridge windows as the bodies of Simone and the other Primes float away into deep space.