The storyline also has three sub storylines within Big Time called Kill To Be You taking place in issues #648 - 651. The Revenge of the Spider-Slayer taking place in #652 - #654, and finally No One Dies taking place within issues #655 and 656 of the Amazing Spider-Man.
Peter takes a new job as researcher at Horizon Labs, and Phil Urich, after killing Daniel Kingsley, becomes the new Hobgoblin. He steals a sample of Reverbium (an experimentally created form of Vibranium metal) from Horizon Labs for the Kingpin. and creates a Lunatic Laugh weapon which Spider-Man has a extremely hard time combating.
Peter, with the help of Horizon Lab equipment, creates a new suit dubbed the "Big Time" suit in order not to be affected by the screams to defeat the new Hobgoblin. Spider-Man teams with Black Cat to get the stolen metal back.
Alistair Smythe has created a new army of Spider-Slayers by giving cybernetic implants to people with a grudge against J. Jonah Jameson. All of the Spider-Slayers, and Mac Gargan as the Scorpion with a new suit, have a sense similar to Spider-Man's spider-sense that makes them harder to hit.
Alistair Smythe targets J. Jonah Jameson's family and friends so that Jameson can feel the same pain Smythe felt when he lost his father. The New Avengers start to help Spider-Man fight the Slayers, but after a string of losses, Peter builds a bomb that will destroy the "spider-sense" power of the Spider-Slayers so they can be defeated.
However, Mac Gargan prevents Spider-Man from escaping after he sets off the bomb, so he is forced to set it off while he is still within the bombs radius and Peter loses his spider-sense power too. After his army of Spider-Slayers is stopped, Smythe attempts to kill Jameson himself, but Marla Jameson jumps in the way to save the life of her husband.
After Alistair Smythe is put away, a funeral is held for Marla Jameson where Peter is present and feels bad for the death of her. That same night, Peter has a nightmare where he sees everyone who has ever died in his life (including Gwen Stacy, Ben Reilly, Ezekiel, Frederick Foswell, Bennett Brant, George Stacy, and Charlamange from Spider-Man Vs. Wolverine). When Peter finally wakes up, he decides to become a better Spider-Man by vowing that "as long as he's around no one dies".
After this vow, he faces off against Massacre, a new villain who has no emotion and whose soul purpose is to kill. Without his spider-sense, Peter is shot by Massacre in a fight.
Peter then builds a new Spider-Armor to combat Massacre. Using this new armor, he defeats the villain and confronts Jameson about his new stance, who wants to give the death penalty to Smythe for killing Marla and to Massacre for all the people he killed.