The worldwide prevalence of uncomplicated infections of the lower urinary tract (uUTIs) caused by multidrug-resistant E. coli is increasing. To address this emergency, international guidelines recommend reducing the administration of fluoroquinolones, considering the growing resistance and their long-lasting and potentially disabling side effects, in favor of fosfomycin trometamol (FT), a well-known derivate of phosphonic acid with a broad-spectrum activity against Gram-negative and Gram-positive bacteria, including multidrug-resistant strains. Recently, the European Committee on Antimicrobial Susceptibility Testing (EUCAST) has reduced the susceptibility breakpoint for E. coli from 32 mg/L to 8 mg/L regarding FT used for uUTIs. This might increase the appropriate use of oral fosfomycin target therapy against E. coli and other microorganisms with a high likelihood of success. For species, such as Klebsiella spp, especially for MDR strains, the absence of clinical breakpoint might lead to a reduction of the use of oral fosfomycin, especially if MIC is not available. To address this issue, this review presents an overview of the available preclinical evidence on the activity of FT, as well as a systematic review of the FT clinical activity used for treating uUTIs in women and, after prostate biopsy, to prevent infectious complications. Our findings suggest that the safety, microbiological and clinical effectiveness of a single oral dose of FT are similar to comparator regimens with longer treatment schedules in women with uUTI, and can also be considered a viable alternative option to fluoroquinolones for antimicrobial prophylaxis in prostate biopsy. These observations and a broad clinical experience support the empirical use of FT for treating uUTI and suggest that FT is a promising candidate to effectively counteract antibiotic-resistant uUTIs throughout Europe.