Neutrophils combat pathogens by intracellular and extracellular processes. Neutrophil extracellular traps (NETs) represent a fascinating mechanism by which neutrophils trap and kill extracellular viruses, bacteria, fungi or parasites. More than two decades passed since the first description of NETs (Brinkmann V, Reichard U, Goosmann C, Science 303:1532–1535, 2004). During this time thousands of reports were published that delivered a large body of information on the mechanism and regulation of NET formation and on their physiological and pathological roles. Numerous receptors, signaling pathways, key molecules, cellular events, well-established and emerging mechanisms have been identified that initiate or promote NET formation. The generation of NETs can be rapid or slow, vital or lethal, driven by NADPH oxidase-derived or mitochondrial oxidants, and be beneficial or detrimental to the host. Despite all this accumulated knowledge, several questions related to NET biology still remain open and demand future investigations. This chapter provides an updated view on the different mechanisms driving NET formation, with a special emphasis on the role of Nox2-generated oxidants.