Urinary tract infections affect more than 1 in 2 women during their lifetime. Among these, more than 10% of patients carry antibiotic-resistant bacterial strains, highlighting the urgent need to identify alternative treatments. While innate defense mechanisms are well-characterized in the lower urinary tract, it is becoming evident that the collecting duct (CD), the first renal segment encountered by invading uropathogenic bacteria, also contributes to bacterial clearance. However, the role of this segment is beginning to be understood. This review summarizes the current knowledge on CD intercalated cells in urinary tract bacterial clearance. Understanding the innate protective role of the uroepithelium and of the CD offers new opportunities for alternative therapeutic strategies.