After the events of Countdown, Frank Castle has been captured by SHIELD and is under therapy by Doc Samson. During a critical phase, Spook interferes and plants the idea in Punisher's head that Nick Fury killed his family. Punisher escapes during an attack by Rosalie Carbone, and proceeds to hunt Fury.
Fury seeks help from the good doctor, but he's busy at the moment with evil powers that dabble with contamination and toxic waste. As he tries to leave, he is approached by criminals who try to persuade him to help them to get the Punisher, but an appearance of SHIELD agents puts a stop to that noise.
Overhearing a conversation that Hulk is having, Punisher's mental condition makes him convinced that a drug lord Wulf Christopher is connected to his family's death. SHIELD makes an appearance as they both crash Christopher's place. Hulk helps Punisher to get away out of spite at SHIELD for the past antagonizations he's had with them.
A traitor in SHIELD’s ranks helps Punisher to destroy one of their warehouses and steal gear. Fury decides to go after Punisher himself, but gets distracted in a critical moment and is seemingly killed by him.