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Neutrophils play a key role in host defense against pathogens. They can contribute to pathological inflammation, and are thought to exacerbate tissue injury upon exposure to bacterial products, such as endotoxin (LPS). Recent findings suggest that neutrophils can also participate in adaptive immune responses and contribute to inflammation resolution. Many discoveries regarding the in vivo role of neutrophils were made possible by the use of genetically modified neutrophil-deficient mice, or by the use of neutrophil-depleting antibodies. Here we describe a new mouse model, PMNDTR mice, in which neutrophils can be selectively depleted upon injection of diphtheria toxin. Using this model, we have recently demonstrated that neutrophils play a protective role during lethal endotoxin-induced systemic shock. This new mouse model presents several major advantages over more classical models of neutropenia, which are discussed herein.