In the past few years, notable advances have occurred in our understanding of the epidemiology and clinical importance of drug resistance among uropathogens that cause uncomplicated urinary tract infections (UTIs) or cystitis. Guidelines recommend trimethoprim-sulfamethoxazole for empirical treatment of uncomplicated UTI unless trimethoprim-sulfamethoxazole resistance in a community exceeds 10% to 20%. The rationale for this 10% to 20% cutoff appears to be related to clinical and economical considerations and to concerns about the emergence of fluoroquinolone-resistant bacteria. In patients with uncomplicated UTIs caused by uropathogens resistant to trimethoprim-sulfamethoxazole who were treated with this drug combination, clinical outcomes were clarified recently and found to be suboptimal (<60% clinical cure). Following guidelines for empirical treatment of uncomplicated UTIs is problematic. Surveillance of antimicrobial resistance among uropathogens that cause uncomplicated UTIs is performed rarely. Hospital antibiograms provide data on resistance among bacteria that cause community-associated UTIs; however, antibiograms overestimate drug resistance among uropathogens that cause UTIs and may mislead clinicians about the prevalence of local resistance. We review options for management of uncomplicated UTIs in light of these considerations.