On the first day of The Rising, struggling single Seattle mother Vanessa Seward was attacked and seemingly killed by a vampire named Balthazar. Balthazar was sent by Dmitri in response to Vanessa's blood sample at a local clinic being responsible for turning a vampire back into a human.
Vanessa was sent to a local hospital, becoming separated from her young daughter, Dylan. Here we meet Doc, whose report of the strange properties of Vanessa's blood prompted a military investigation. Before the soldiers could extract Vanessa's body, vampires attacked the hospital.
Three years later, Axel is the lone military man holing up in the hospital, feeding his own blood to Doc, who has since been turned into a vampire. Vanessa has been in a coma all this time, though Axel is still honoring his mission to protect her.
The arrival of a ragtag group of survivors leads to another vampire attack at the hospital. A vampire named Flesh bites Vanessa, which brings her out of her coma (and turns him back into a human). She shows off some mad superpowers: rapid healing abilities, super-strength and, of course, kung fu! The vampire community is very interested in this mystery woman with the power to reverse the effects of vampirism … and more than a little afraid of her, too.
After turning Doc back into a human, Vanessa visits her old apartment, accompanied by another survivor named Mohamad, hoping to find clues as to the whereabouts of her daughter, Dylan. It would appear that Dylan made it out of the apartment after Vanessa was attacked … but where is she?
Vanessa is later captured and taken to Julius' nightmarish compound, where she's reunited with her neighbor, Susan. Vanessa bites Susan, turning her back into a human, and the two of them escape back to the hospital.
There's a brief but deadly power struggle at the hospital when another group of survivors led by a man named Brendan imprisons Axel and the gang over concerns of a mystery killer that seems to be picking everyone off one by one. When Vanessa returns to the hospital, Axel escapes and guns down most of Brendan's group, exiling Brendan and his remaining followers to the outside world.
Julius eventually stages a siege of the hospital, which leads to the gang hitting the road. Their first stop is an underground bunker near Axel's old military base known as The Farm, the location of top-secret experiments and research. There, evidence points to the mystery killer being a survivor named John, and he's killed after threatening Susan with a broken beer bottle.
The gang soon discovers that The Farm is contaminated with radiation ... and Axel is seemingly killed by a vampire during the evacuation. Doc is haunted by her leaving Axel to die, an act of cowardice that reminds her of the self-preserving selfishness that led to her being bitten by a vampire years earlier.
The next stop for the gang is Eden, a utopian community where Vanessa enjoys a brief romance with the handsome Theo. It's also in Eden where Flesh seemingly finds peace of mind after being long haunted by his previous tenure as a vampire … and where the gang is reunited with Mohamad, who had been exiled from the hospital by Brendan.
Eden hides a dark secret, though: a blood pact with Magdalena, a vampire who lets the denizens of Eden live in peace in exchange for human infants on which to feed. Vanessa breaks this pact and Flesh stays behind to rebuild Eden under more … well, utopian circumstances.
After the guilt-ridden Doc breaks off from the group, the gang arrives at Susan's family farm, where the true mystery killer is finally revealed: Sam, the deaf giant. Sam's final victim is poor Susan, after which Vanessa and a heartbroken Mohamad leave him in the woods to die.
Sam's reign of terror recommences tenfold after he's bitten by a Feral, which turns him into a vampire … and one that can hear! He stalks Vanessa and Mohamad before being brought to Julius' camp, where he becomes acquainted with Julius' mama. When Julius returns to camp, he discovers that his mother has been killed … with Sam nowhere to be found.
Vanessa and Mohamad infiltrate a vampire camp, where Vanessa hopes to find her daughter Dylan. Vanessa soon realizes she's been sold out to Dmitri by Mohamad in exchange for being reunited with Mohamad's long-lost sister, Sheema.
Mohamad is heartbroken by his betrayal … and even more heartbroken to discover that Sheema is in cahoots with the power-hungry Rebecca. Mohamad tries to get Sheema to leave the vampires' Citadel with him but she responds with knocking him out with a candle holder.
Dmitri tells the imprisoned Vanessa her real identity: she's a Van Helsing, descendant of Abraham Van Helsing (the fearless vampire killer of Dracula lore). Dmitri's planning on using Vanessa's blood and eggs for all sorts of horrible experiments that will hopefully result in vampires being able to walk around in daylight and procreate.