Chronic rhinosinusitis (CRS) is a chronic inflammatory disease of the nose and sinuses that affects up to 12% of the population in Europe and the United States. This complex disease is likely driven by multiple environmental, genetic, and inflammatory mechanisms, and recent studies suggest that B cells might play a critical role in disease pathogenesis. B cells and their antibodies have undisputed roles in health and disease within the airway mucosae. Deficient or inadequate B-cell responses can lead to susceptibility to infectious disease in the nose, whereas excess antibody production, including autoantibodies, can promote damaging inflammation. Thus, patients with B-cell defects often have either chronic or recurrent acute infections, and this can be associated with nonpolypoid CRS. In contrast, many patients with CRS with nasal polyps, which is less likely to be driven by pathogens, have excess production of local immunoglobulins, including autoreactive antibodies. These B-cell responses activate complement in many patients and likely contribute to immunopathogenic responses. A better understanding of the B cell–associated mechanisms that drive disease in patients with CRS should be a high priority in the quest to understand the pathogenesis of this disease.