Neutrophils are terminally differentiated leukocytes, specialized in detecting and annihilating possible pathogens. For this function, neutrophils contain a number of cytotoxic systems, which can both kill the intruder or promote extensive tissue injury. The most stereotyped neutrophil cytotoxic mechanism is the extracellular and intra-phagosomal production of high amounts of superoxide (O2-) and other reactive oxygen species (ROS) via the activation of the complex NADPH oxidase (NADPHox). It has been proposed that the short neutrophil lifespan would be a mechanism of counter-regulating the indiscriminate release of its cytotoxic content, as well as aborting the excessive production of ROS. Studies performed in the last decades point out the role of NADPHox activity as one of the major systems involved in the up-regulation of neutrophil apoptosis. However, a growing number of evidence suggests that NADPHox-derived ROS are involved in the activation of signaling pathways that may lead to increased neutrophil survival. In this review, we evaluate the implication of NADPHox activity in the control of neutrophil's life and death, highlighting the signaling pathways modulated by NADPHox-derived ROS.