Most otolaryngologists encounter patients with chronic rhinosinusitis who, despite conventional medical and surgical therapy, fail to show significant symptomatic improvement. Many paradigms have been proposed to explain the mechanisms responsible for refractory disease in these patients, including superantigen activation, biofilm formation, and eosinophil activation triggered by fungal elements. Although the precise underlying etiology of this clinical scenario remains unclear, the resultant pathophysiologic events share a final common pathway marked by inflammatory changes of the sinonasal mucosa. This article reviews the proposed hypotheses as to why some patients with chronic sinusitis fail conventional therapy and highlights treatment options useful in the palliative treatment of these patients.