Acute pyelonephritis is a bacterial infection of the kidney and renal pelvis and should be suspected in patients with flank pain and laboratory evidence of urinary tract infection. Urine culture with antimicrobial susceptibility testing should be performed in all patients and used to direct therapy. Imaging, blood cultures, and measurement of serum inflammatory markers should not be performed in uncomplicated cases. Outpatient management is appropriate in patients who have uncomplicated disease and can tolerate oral therapy. Extended emergency department or observation unit stays are an appropriate option for patients who initially warrant intravenous therapy. Fluoroquinolones and trimethoprim/sulfamethoxazole are effective oral antibiotics in most cases, but increasing resistance makes empiric use problematic. When local resistance to a chosen oral antibiotic likely exceeds 10%, one dose of a long-acting broad-spectrum parenteral antibiotic should also be given while awaiting susceptibility data. Patients admitted to the hospital should receive parenteral antibiotic therapy, and those with sepsis or risk of infection with a multidrug-resistant organism should receive antibiotics with activity against extended-spectrum beta-lactamase-producing organisms. Most patients respond to appropriate management within 48 to 72 hours, and those who do not should be evaluated with imaging and repeat cultures while alternative diagnoses are considered. In cases of concurrent urinary tract obstruction, referral for urgent decompression should be pursued. Pregnant patients with pyelonephritis are at significantly elevated risk of severe complications and should be admitted and treated initially with parenteral therapy.