Neutrophil extracellular traps (NETs) are extracellular structures composed of chromatin and granule proteins that bind and kill microorganisms. This study shows that upon stimulation, neutrophil nuclei lose their shape, and the eu- and heterochromatin homogenize. Later, the nuclear envelope and granule membranes disintegrate, allowing the mixing of NET components. Finally, the NETs are released as the cell dies. This novel cell death program is distinct from apoptosis and necrosis and depends on the generation of reactive oxygen species (ROS) by NADPH oxidase. Patients with chronic granulomatous disease (CGD) carry mutations in NADPH oxidase and cannot activate this cell-death pathway or make NETs. This ROS-dependent death allows neutrophils to fulfill their antimicrobial function beyond their lifespan. Neutrophils are the first line of defense against invading microbes. When they reach the circulation, they are already equipped with proteins to kill microorganisms. Upon encountering pathogens, neutrophils activate and engulf the pathogen into a phagosome. In the phagosome, two events are required for antimicrobial activity: the assembly of NADPH oxidase subunits to produce superoxide anions and the fusion of granules with the phagosome to discharge antimicrobial peptides and enzymes. These events lead to the formation of reactive oxygen species (ROS) and antimicrobial peptides, which are responsible for microbial killing. Recently, a novel antimicrobial mechanism was described: neutrophils release extracellular traps (NETs) upon activation. NETs are composed of chromatin decorated with granular proteins and bind Gram-positive and -negative bacteria, as well as fungi. These structures provide a high local concentration of antimicrobial molecules that kill microbes effectively. NETs are abundant at inflammatory sites and have been shown to be relevant in vivo in human preeclampsia and streptococcal infections. The release of intact chromatin decorated with cytoplasmic proteins into the extracellular space is unprecedented. Activated neutrophils initiate a process where the classical lobulated nuclear morphology and the distinction between eu- and heterochromatin are lost. Later, all internal membranes disappear, allowing NET components to mix. Finally, NETs emerge from the cell as the cytoplasmic membrane is ruptured by a process distinct from necrosis or apoptosis. This active process is dependent on the generation of ROS by NADPH oxidase. In an infection, ROS formation may contribute to the following two antimicrobial pathways: intraphagosomal killing in live neutrophils and NET-mediated killing post mortem. The study shows that NET formation is a distinct form of cell death, different from apoptosis and necrosis. Neutrophils that form NETs exhibit morphological changes such as the disintegration of the nuclear envelope and the mixing of nuclear and cytoplasmic components. The release of NETs is dependentNeutrophil extracellular traps (NETs) are extracellular structures composed of chromatin and granule proteins that bind and kill microorganisms. This study shows that upon stimulation, neutrophil nuclei lose their shape, and the eu- and heterochromatin homogenize. Later, the nuclear envelope and granule membranes disintegrate, allowing the mixing of NET components. Finally, the NETs are released as the cell dies. This novel cell death program is distinct from apoptosis and necrosis and depends on the generation of reactive oxygen species (ROS) by NADPH oxidase. Patients with chronic granulomatous disease (CGD) carry mutations in NADPH oxidase and cannot activate this cell-death pathway or make NETs. This ROS-dependent death allows neutrophils to fulfill their antimicrobial function beyond their lifespan. Neutrophils are the first line of defense against invading microbes. When they reach the circulation, they are already equipped with proteins to kill microorganisms. Upon encountering pathogens, neutrophils activate and engulf the pathogen into a phagosome. In the phagosome, two events are required for antimicrobial activity: the assembly of NADPH oxidase subunits to produce superoxide anions and the fusion of granules with the phagosome to discharge antimicrobial peptides and enzymes. These events lead to the formation of reactive oxygen species (ROS) and antimicrobial peptides, which are responsible for microbial killing. Recently, a novel antimicrobial mechanism was described: neutrophils release extracellular traps (NETs) upon activation. NETs are composed of chromatin decorated with granular proteins and bind Gram-positive and -negative bacteria, as well as fungi. These structures provide a high local concentration of antimicrobial molecules that kill microbes effectively. NETs are abundant at inflammatory sites and have been shown to be relevant in vivo in human preeclampsia and streptococcal infections. The release of intact chromatin decorated with cytoplasmic proteins into the extracellular space is unprecedented. Activated neutrophils initiate a process where the classical lobulated nuclear morphology and the distinction between eu- and heterochromatin are lost. Later, all internal membranes disappear, allowing NET components to mix. Finally, NETs emerge from the cell as the cytoplasmic membrane is ruptured by a process distinct from necrosis or apoptosis. This active process is dependent on the generation of ROS by NADPH oxidase. In an infection, ROS formation may contribute to the following two antimicrobial pathways: intraphagosomal killing in live neutrophils and NET-mediated killing post mortem. The study shows that NET formation is a distinct form of cell death, different from apoptosis and necrosis. Neutrophils that form NETs exhibit morphological changes such as the disintegration of the nuclear envelope and the mixing of nuclear and cytoplasmic components. The release of NETs is dependent