Cystic fibrosis (CF) lung disease is characterized by persistent and unresolved inflammation, with elevated proinflammatory and decreased anti-inflammatory cytokines, and greater numbers of immune cells. Hyperinflammation is recognized as a leading cause of lung tissue destruction in CF. Hyper-inflammation is not solely observed in the lungs of CF patients, since it may contribute to destruction of exocrine pancreas and, likely, to defects in gastrointestinal tract tissue integrity. Paradoxically, despite the robust inflammatory response, and elevated number of immune cells (such as neutrophils and macrophages), CF lungs fail to clear bacteria and are more susceptible to infections. Here, we have summarized the current understanding of immune dysregulation in CF, which may drive hyperinflammation and impaired host defense.