The series opens a few months after the death of Elena Gilbert's parents in the town of Mystic Falls, Virginia. As the new school year starts, Elena meets new student Stefan Salvatore who turns out to be a vampire. Elena and one of her best friends, Caroline Forbes each become interested in Stefan, and soon Stephen's brother Damon Salvatore, who is also a vampire, comes into the picture as the primary antagonist of the first season.

In the second season, we learn that the Salvatore brothers' attraction to Elena stems from relationships they had with her doppelgänger Katherine Pierce in Civil War Era Mystic falls. It turns out that Katherine is the reason that Stephen and Damon became Vampires, and they had both loved her, and now had to know this new lookalike. When Katherine is released from an ancient tomb, among other things, she kills Caroline but this results in Caroline being turned into a Vampire. By the end of the season, Klaus Mikaelson, one of the original vampires, turns up in Mystic Falls.

Throughout the next season Klaus becomes the main antagonist and needs to use Elena's blood to break the binding of his werewolf curse. Having unleashed his full strength, he now sees the opportunity to use Elena to sire vampire-werewolf hybrids and create an army to do his bidding. This power comes to an end when an accident leaves Elena herself becoming a vampire.

As the Salvatore brothers along with Caroline help Elena with the transition into life as a vampire, the Mikaelson family remains in Mystic Falls. Amongst other things, the Mikaelson's join forces with the Salvatore's in search of the cure for vampirism to give Rebekah and Elena respectively. When Klaus' relationship with werewolf Hayley Marshall results in a loophole pregnancy, the remaining Mikaelson's leave to New Orleans where The Originals takes place.

Throughout the next few seasons, as Elena and Caroline go to college, they encounter various supernatural adventures, aided by a variety of friends. Notably, the characters become involved with the witches of the Gemini Coven. This results in Alaric Saltzman unborn twin children of the Gemini bloodline to be magically transferred to Caroline's womb at the time of their mother's murder. In addition, the chaos caused at the Coven's fall resulted in Elena being placed in an enchanted sleep, allowing Nina Dobrev to leave the show for the next season.

The show then skips several years, and among some flashbacks we see that several relationships have changed, but overall the Salvatore brothers are defending themselves from supernatural peril and searching for a way to wake Elena from the magical sleep and administer the cure for vampirism. A sequence of magical loopholes and sacrifices allows Elena and Damon to be cured, and start a normal human life in Mystic Falls.

As the Mikaelson family returns to their former home of New Orleans in lieu of the birth of Klaus' unborn daughter, they must face their old friend Marcel Gerard, who became the supernatural leader of the town after they fled the previous century. The family finds their return unwelcome, especially by the town witches who fear that the unborn child may cause too many problems and supernatural imbalance. At the end of the first season, Hayley gives birth to Hope Andrea Mikaelson. Hope's tribrid nature of a werewolf mother and hybrid father of which descent results in her birth turning Hayley into a hybrid.

With the New Orleans witches and vampires both being fearful of Klaus giving the town werewolves the power of becoming hybrids, Klaus and Hope are seen as a threat. A partial result of this is the witch Davina Clair summoning Klaus' vampire killing father Mikel to eliminate Klaus. Eventually Klaus is able to kill his father once and for all and protect his family.

Among various supernatural enemies that the Mikaelson's must fend off in their new home, the biggest threat comes when an extremely powerful evil force known as the Hollow inhabits Hope's body. It's concluded that the only solution is to divide the Hollow into four pieces, and secure each in Klaus, Rebekah, Elijah, and Kol. The siblings must then all flee to be as far apart as they can from each other and hope, to keep the Hollow from reentering her.

The final season begins when Hope is 15 and safely attending the Salvatore Boarding School for the supernatural in Mystic Falls, set up by Alaric and Caroline to help young vampires, witches and werewolves like their daughters. Having been safe from the Hollow for several years, Hope is put in danger when Klaus continues to visit a memory wiped Elijah, and the forces start to release. In danger of causing the death of all firstborns if the siblings continue to be in close contact with each other or Hope, action must be taken. Initially, Hope chooses to reabsorb the Hollow into her own body, and briefly uses the power to take care of some purist vampires trying to kill her family. In the process, she activates her werewolf curse, and soon Klaus realizes that the Hollow has to be removed from Hope. They travel to Mystic Falls where they get the Saltzman twins to siphon the magic and place it into Klaus' body. Knowing that the power had to be destroyed, it's decided that the only possibility for Hope's survival is his death. The series concludes with the agreed death of Klaus and Elijah at each other's hands.

Alaric Saltzman works as head of the Salvatore Boarding School in Mystic Falls where his daughters Lizzie and Josie attend school with Hope Mikaelson. As the students build relationships with each other, they and Alaric keep discovering new magical problems that they never imagined existed.

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