Chronic rhinosinusitis (CRS) is a heterogeneous inflammatory condition with a multifactorial basis. Infectious triggers of CRS have been proposed, but demonstration remains elusive. Evolving research suggests that abnormal host mucosal immune responses, rather than specific pathogens themselves, may underlie the chronic inflammatory state. Despite constant contact with airborne particulates and microorganisms, the sinonasal epithelium maintains mucosal homeostasis through innate and adaptive immune mechanisms that eliminate potential threats. Innate immunity encompasses a broad collection of constitutive and inducible processes that can be nonspecific or pathogen directed. Some innate immune pathways are closely intertwined with tissue growth and repair. The persistent inflammation observed in CRS may result from a pathologic imbalance in innate immune interactions between the host and the environment. Impairment of critical innate immune protection renders the sinonasal mucosal surface susceptible to colonization and potential injury, stimulating the prominent adaptive immune response that characterizes CRS.