Neutrophils are central regulators of the innate immune response and help shape the adaptive immune response. Malfunction and unregulated neutrophil activation leads to disease and inflammation. During the host response to infection, neutrophils display several mechanisms of defense mediated by their arsenal of granular proteins. Regulation of granular trafficking, docking and fusion is at the core of the neutrophil defense response to pathogens. The small GTPase Rab27a has emerged as a central regulator of the neutrophil response through its tight control of vesicular trafficking and degranulation. This review focuses on the latest research that has led to the characterization of Rab27a as an essential regulator of neutrophil function.