The innate immune system is the first line of host defense against invading microorganisms. Polymorphonuclear leukocytes (PMNs or neutrophils) are the most abundant leukocyte in humans and essential to the innate immune response against invading pathogens. Compared with the acquired immune response, which requires time to develop and is dependent on previous interaction with specific microbes, the ability of neutrophils to kill microorganisms is immediate, non‐specific, and not dependent on previous exposure to microorganisms. Historically, studies on PMN‐pathogen interaction focused on the events leading to killing of microorganisms, such as recruitment/chemotaxis, transmigration, phagocytosis, and activation, whereas post‐phagocytosis sequelae were infrequently considered. In addition, it was widely accepted that human neutrophils possessed limited capacity for new gene transcription and thus, relatively little biosynthetic capacity. This notion has changed dramatically within the past decade. Further, there is now more effort directed to understand the events occurring in PMNs after killing of microbes. Herein we review the systems biology‐level approaches that have been used to gain an enhanced view of the role of neutrophils during host‐pathogen interaction. We anticipate that these and future systems‐level studies will ultimately provide information critical to our understanding, treatment, and control of diseases caused by pathogenic microorganisms. Copyright © 2009 John Wiley & Sons, Inc.

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• Physiology > Organismal Responses to Environment