Chronic rhinosinusitis (CRS) is a persistent inflammatory condition involving the nasal and paranasal mucosa. It is the most prevalent chronic condition in the United States. Sinonasal inflammation is also a common clinical presentation in a variety of systemic conditions. The etiology of CRS is complicated as a variety of extrinsic and intrinsic factors are frequently involved. Extrinsic factors include microbial infections that trigger abnormal immune responses. Intrinsic factors may predispose an individual to infection or exaggerated inflammatory responses. Several systemic conditions such as cystic fibrosis (CF), primary ciliary dyskinesia (PCD), asthma, immunohyper-responsiveness, and immunodeficiencies illustrate the role of genetic abnormalities in the development of CRS. Both common and rare genetic variants have been found in an association with CRS. A role for genetic factors is also supported by the demonstration of CRS clustering in families. Although the majority of CRS cases are considered to be idiopathic, the pathological evidence suggests that the chronic condition could be an overlapped presentation of multiple underlying mechanisms. Systemic conditions may have an impact on the incidence, severity, prognosis, or treatment of patients with CRS. Evaluation for underlying conditions may help the otolaryngologist manage the symptoms of CRS and optimize therapy.