Neutrophils play a pivotal role in the innate immune response to microbial pathogens. They are uniquely suited to this role by virtue of specialized antimicrobial capabilities that include the capacity to sense minute amounts of microbial products and inflammatory mediators, to move to the site of infection, and finally to bind, internalize and kill the pathogens. To optimize host defense capabilities while minimizing damage to host tissues ('collateral damage'), these microbicidal responses must be tightly regulated. Additionally, neutrophils clear inflammatory debris, a process that is necessary for restoration of the native architecture and function of the tissue. This review highlights some recent advances in our knowledge of cell signaling as it pertains to neutrophil function, with specific emphasis on the role of the phosphatidylinositide 3-kinase in antimicrobial function.