There has been considerable investigation of host-microbial interactions in patients with chronic rhinosinusitis (CRS) in hopes of elucidating mechanisms of disease and better treatment. Most attention has been paid to bacterial infection and potential underlying defects in innate immunity. Bacterial biofilm is present in most patients with CRS undergoing surgical intervention, and its presence is associated with more severe disease and worse surgical outcomes. A role for viral or fungal infection in patients with CRS is less clear. There is no evidence for a primary defect in mucociliary clearance in most patients with CRS. Decreased levels of certain antimicrobial proteins, most notably lactoferrin, have been found in sinus secretions, whereas levels of other antimicrobial proteins have been found to be normal. No primary defects in Toll-like receptors have been found in patients with CRS, although a 50% reduced expression of Toll-like receptor 9 was reported in patients with recalcitrant nasal polyps. A polymorphism in a bitter taste receptor was recently associated with refractory CRS and persistent Pseudomonas aeruginosa infection. A downregulation of innate immunity by maladaptive T H2 tissue inflammation has also been described in patients with recalcitrant nasal polyps, suggesting a link to persistent infection. To date, an effective means of restoring host-microbial balance and mitigating disease in patients with CRS remains elusive.