Chronic rhinosinusitis (CRS) is a prevalent health condition characterized by sinonasal mucosal inflammation lasting at least 12 weeks. Heterogeneous in clinical presentation, histopathology, and therapeutic response, CRS represents a spectrum of disease entities with variable pathophysiology. Increased knowledge of cellular and molecular derangements in CRS suggests potential etiologies and targets for therapy. Microbial elements including fungi, staphylococcal enterotoxin, and biofilms have been implicated as inflammatory stimuli, along with airborne irritants and allergens. Defects in innate immunity have gained increased attention as contributors to the chronic inflammatory state. A combination of host susceptibility and environmental exposure is widely believed to underlie CRS, although direct evidence is lacking. Presently, without precise disease definitions and identifiable universal triggers, CRS pathogenesis is broadly described as multifactorial. Current research is beginning to unravel complex and diverse effects of chronic inflammation on sinonasal mucosal homeostasis, but dysfunctional pathways of inflammatory regulation and resolution require further elucidation.