The book begins with Jack having turned Meredith into a genetic vampire after kidnapping her. She escapes though, but begins to get the craving for human blood. Damon and Elena both desire vengeance on Jack for killing Stefan, so they spend much of the book trying to figure out how to kill him. Damon notices how they are strong and fast, but not like him and are unkillable. Damon fights Jack and realizes Jack is somehow stronger than his own creations despite being a genetic vampire. Damon loses the fight, but finds out snapping their necks will neutralize them for a while. Meredith continues to hunger for blood and Alaric notices something is wrong with her but she refuses to tell him. Matt also reveals he is now dating Jasmine, who is a doctor and accepts everything about him, even the supernatural aspects he deals with.
The guardian Mylea comes to Elena telling her she has to track down and kill an old vampire named Siobhan. Elena tries but fails to find her a few times. She also attempts to come in contact with Stefan through Bonnie's help but fails twice. Damon decides to send Meredith to join Jack's gang to gain info on how to kill him and his creations. Meredith joins and he takes her in. Jack, Meredith and 4 other genetic vampires, Adam, Nick, Conrad and Sadie hunt down a pack of vampires in which Jack kills the oldest members. Jack tells Nick to find "her" and after he fails, he stabs Nick as a warning to make sure he does it right next time.
It's revealed by Jack to Meredith that the only way to kill one of them is by stabbing them in the back of the head where a scar is and that it should kill them. She takes this info back to Damon who has captured one of the creations and has been torturing him with different ways to kill a vampire. Damon stabs the vampire in his scar but it only angers and hurts him. Jack comes in and reveals he gave Meredith this false info to test her and she fails. Jack and his creations battle Damon and friends, frees his prisoner and leaves. Later after the loss, Alaric returns with some info, talking about how Jack's experiments go back to Zurich 5 years ago. He also says Jack has been a vampire for 3 years and his real name is not Jack Daltry as it was revealed earlier in the book but actually Henrik Goetsch.
Zander proposes to Bonnie to marry him and asks her to come to Colorado to join him and his pack but she refuses, saying her friends need her here to deal with Jack. He then breaks up with her. However, she does accept his marriage later on and says after she is done helping her friends with Jack, she will join him and his pack. Jasmine does some research in her lab and compares Damon's blood to the blood of one of Jack's creations. She reveals that they are almost exactly alike and that vampire blood was used to create his vampires. Later, Jack goes to Jasmine's apartment and tells Matt he has kidnapped Jasmine and will return her if Matt brings Damon to him. Matt decides to trade his life for Jasmine in which Jack accepts. Damon and Elena eventually do find Siobhan through a spell from Bonnie using the genetic vampire blood.
Siobhan is the vampire whom Jack used to make his creations. It's revealed that she loved Jack but he loved someone else, so she kills his lab assistant and killed Lucia, also swearing to kill Jack. She reveals the only thing that can kill him is this blue poison from a vial only she has on her. They go to Dalcrest College to confront and kill Jack. Damon battles him and stabs him with the vial but it's revealed to only make him stronger and that Siobhan tricked them, telling them she loves Jack and will kill him on her terms. Elena then kills Siobhan as she was going to originally do after they were done needing her. In the meantime, Jack escapes. Damon and Elena go back to Zurich to go through his lab since that is where they found his notebook. Elena and Damon bond and end up kissing. Elena goes to a guard in which the lab is located, she finds out she can compel vampires as he is one of the genetic vampires but it will only work as she doesn't break concentrations. Through a series of events, she finds a black box of 6 vials of blue poison and realizes this is the real poison. She uses it on the guard, which kills him. Jack is then revealed to have gone to Zurich as well, which leads to a final fight.
Jack and Damon end up fighting, while Elena uses her guardian powers to help Damon fight off Jack. Damon, who is nearly killed by Jack, ends up taking one of the blue poison vials and stabs it into Jack's neck. Jack, as he lays dying, tells Damon and Elena he only made his creations because Siobhan killed Lucia and he wanted revenge on her and her race, so he made his own vampires and when he was done killing the magical vampires, he was going to kill his own creations. Elena and Damon seem to have no pity for him and he finally dies.
Weeks later, Zander ends up marrying Bonnie. Alaric rejects a cup of water that can make him immortal to be with Meredith forever and vows to find a cure to rid her of vampirism. Later on, Elena goes to her childhood home, the place Stefan had planned for her. She goes in only to find Stefan in spirit form and he was waiting for her in the house. They have one final kiss and part ways forever.
Damon and Elena go to Paris but Elena begins to choke. Mylea the guardian, goes to them stating that because Damon killed a human (she states Jack was a human even if he used science to make himself a vampire), the bond between him and Elena is broken and she will die. Mylea leaves and Damon vows to save Elena no matter what it takes. The Book ends.