The increase in resistance rates to TMP/SMX among E. coli causing community-acquired UTI has resulted in consideration of alternative agents as first line therapy for these infections. However, there has been little study of the clinical significance of the in vitro trends in resistance which have been reported. We review studies that address the correlation between in vitro resistance to TMP/SMX and clinical outcome in uncomplicated UTI. From these data, it is clear that in vitro resistance does translate into therapeutic failure for 50-60% of patients with a TMP/SMX resistant uropathogen. Thus, it is reasonable to consider an agent other than TMP/SMX when the TMP/SMX resistance prevalence reaches 20%.