Nitrofurantoin is considered a first-line antimicrobial agent by the AUA/CUA/SUFU Guideline and Infectious Disease Society of America (IDSA) Guideline for the treatment of acute uncomplicated simple cystitis in women. Nitrofurantoin has good oral bioavailability, high concentration in urine, and low serum and tissue concentrations. These characteristics result in minimal collateral damage to the microbial composition of other niches within the human body, such as the gut, that are essential in maintaining homeostasis. In addition, resistance to nitrofurantoin is uncommon owing to its interference with multiple bacterial cellular functions critical to survival. Large systematic reviews and meta-analyses have demonstrated that nitrofurantoin is noninferior to other commonly prescribed antibiotics for treatment of urinary tract infection (UTI). Recent data from a randomized controlled trial suggest that a 5-day course of nitrofurantoin may be more effective than a single dose of fosfomycin in the treatment of UTI. Therefore, nitrofurantoin is an ideal first-line agent in the management of UTI.