Antimicrobial therapy has been a mainstay of treatment for chronic rhinosinusitis (CRS). The roles of bacterial and fungal infection in the primary pathogenesis of CRS recently have been called into question. Although many different bacteria and fungi can be isolated from CRS patients, antimicrobial treatment directed at their eradication has met with mixed clinical results. Overall, macrolide antibiotics hold the most promise before surgery. Topical antibiotics are safe, efficient, and effective for treating acute bacterial exacerbations of CRS after endoscopic sinus surgery and may prevent the development of subsequent bacterial resistance. Topical treatment of CRS with antifungal agents both before and after sinus surgery is of limited benefit and should not be considered as a primary treatment modality before surgery. Further research into the role of bacterial and fungal infection in the pathophysiology of CRS may offer better insights into appropriate antimicrobial choices, dosing, and treatment duration.