Cystic fibrosis (CF) is the most frequent recessive disease in Caucasians. While CF affects all exocrine organs throughout the body, its lung manifestation represents the main cause of morbidity and mortality. Key studies have demonstrated that neutrophilic inflammation occurs early in the course of CF lung disease and that neutrophil-derived factors, most notably elastase, play a crucial pathological role. However, the exact mechanism of neutrophilic inflammation remains unclear. Are there distinct inflammatory phases in the multidecade-long course of CF lung disease? Are CF neutrophils intrinsically abnormal or conditioned by neighboring cells? What is the role of live versus post-apoptotic lung neutrophils? These are some of the questions that this review addresses. This review also argues that the current paradigm that views neutrophils as short-lived indiscriminate killers is seriously flawed. Thus, researchers and clinicians need to view the pathophysiological importance of neutrophils in a new light, to the ultimate benefit of patients.