Polymorphonuclear leukocytes (PMNs or neutrophils) are essential components of the innate immune system in humans and function primarily to eliminate invading microorganisms. Neutrophil influx to sites of infection is desirable because it also initiates an inflammatory response. Paradoxically, PMNs are also intimately associated with inflammatory disease. As part of normal neutrophil turnover in humans and to limit inflammatory potential, PMNs undergo programmed cell death, or apoptosis. Several host factors, including cytokines and growth factors, are capable of extending neutrophil survival and, thus, capacity to fight infection. On the other hand, phagocytosis of bacterial pathogens generally accelerates PMN apoptosis. Due in part to the extensive complexity of programmed cell death, relatively little is known about the signaling pathways that govern these processes in PMNs. Recently, microarray strategies have been employed to gain an understanding of these processes in activated PMNs, and new evidence indicates that gene transcription is important in the regulation of neutrophil apoptosis and, thus, inflammation. A series of provocative discoveries led to the hypothesis that neutrophil programmed cell death is the result of an apoptosis-differentiation program, a final stage of transcriptionally regulated PMN maturation or hematopoietic differentiation. Further characterization of the apoptosis-differentiation program and associated biochemical pathways in mature PMNs will likely yield important insights into the resolution of inflammation and infection.