Acute uncomplicated UTI is one of the most common problems for which young women seek medical attention and accounts for considerable morbidity and health care costs. Acute cystitis or pyelonephritis in the adult patient should be considered uncomplicated if the patient is not pregnant or elderly, if there has been no recent instrumentation or antimicrobial treatment, and if there are no known functional or anatomic abnormalities of the genitourinary tract. Most of these infections are caused by E. coli, which are susceptible to many oral antimicrobials, although resistance is increasing to some of the commonly used agents, especially TMP-SMX. In women with risk factors for infection with resistant bacteria, or in the setting of a high prevalence of TMP-SMX-resistant uropathogens, a case can be made for using a fluoroquinolone or nitrofurantoin. Use of nitrofurantoin for the empiric treatment of mild cystitis is supportable from a public health perspective in an attempt to decrease uropathogen resistance because it does not share cross-resistance with more commonly prescribed antimicrobials. Beta-lactams and fosfomycin should be considered second-line agents for empiric treatment of cystitis. Acute pyelonephritis in an otherwise healthy woman may be considered an uncomplicated infection. Fluoroquinolone regimens are superior to TMP-SMX for empiric therapy because of the relatively high prevalence of TMP-SMX resistance among uropathogens causing pyelonephritis. TMP-SMX, effective for patients with mild to moderate disease, is an appropriate drug if the uropathogen is known to be susceptible. It is reasonable to use a 7- to 10-day oral fluoroquinolone regimen for outpatient management of mild to moderate pyelonephritis in the setting of a susceptible causative pathogen and rapid clinical response to therapy. Most women with acute uncomplicated pyelonephritis are now managed safely and effectively as outpatients. Acute uncomplicated cystitis or pyelonephritis in healthy adult men is very uncommon but is generally caused by the same spectrum of uropathogens with the same antimicrobial susceptibility profile as that seen in women. The choice of antimicrobials is similar to that recommended for cystitis in women except that nitrofurantoin is not considered a good choice. Treatment duration should generally be longer than that recommended for women.